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Sample records for acetaminophen-induced acute hepatotoxicity

  1. Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity

    DEFF Research Database (Denmark)

    Schmidt, L.E.; Dalhoff, K.P.; Poulsen, Henrik E.

    2002-01-01

    . With a time to NAC less than 12 hours, the mortality rate was 0.42% (95% CI, 0.05-2.7). When time to NAC exceeded 12, 24, and 48 hours, the mortality rate increased to 6.1%, 13%, and 19%, respectively. Chronic alcohol abuse was an independent risk factor of mortality (odds ratio [OR], 3.52; 95% CI, 1...... was confirmed as the major risk factor in acetaminophen-induced hepatotoxicity and mortality. Chronic alcohol abuse was an independent risk factor that could be counteracted by concomitant acute alcohol ingestion. We suggest that patients with chronic alcoholism and suspected acetaminophen poisoning due......The aim of this study was to determine by multivariate analysis how alcohol and other factors affect the clinical course and outcome in patients with acetaminophen (paracetamol) poisoning. A total of 645 consecutive patients admitted from 1994 to 2000 with single-dose acetaminophen poisoning were...

  2. Zingiber officinale Roscoe prevents acetaminophen-induced acute hepatotoxicity by enhancing hepatic antioxidant status.

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    Ajith, T A; Hema, U; Aswathy, M S

    2007-11-01

    A large number of xenobiotics are reported to be potentially hepatotoxic. Free radicals generated from the xenobiotic metabolism can induce lesions of the liver and react with the basic cellular constituents - proteins, lipids, RNA and DNA. Hepatoprotective activity of aqueous ethanol extract of Zingiber officinale was evaluated against single dose of acetaminophen-induced (3g/kg, p.o.) acute hepatotoxicity in rat. Aqueous extract of Z. officinale significantly protected the hepatotoxicity as evident from the activities of serum transaminase and alkaline phosphatase (ALP). Serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT) and ALP activities were significantly (pHepatic lipid peroxidation was enhanced significantly (pofficinale (200 and 400mg/kg, p.o.) prior to acetaminophen significantly declines the activities of serum transaminases and ALP. Further the hepatic antioxidant status was enhanced in the Z. officinale plus acetaminophen treated group than the control group. The results of the present study concluded that the hepatoprotective effect of aqueous ethanol extract of Z. officinale against acetaminophen-induced acute toxicity is mediated either by preventing the decline of hepatic antioxidant status or due to its direct radical scavenging capacity.

  3. Necrostatin-1 protects against reactive oxygen species (ROS-induced hepatotoxicity in acetaminophen-induced acute liver failure

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    Kenji Takemoto

    2014-01-01

    Full Text Available Excessive acetaminophen (APAP use is one of the most common causes of acute liver failure. Various types of cell death in the damaged liver are linked to APAP-induced hepatotoxicity, and, of these, necrotic cell death of hepatocytes has been shown to be involved in disease pathogenesis. Until recently, necrosis was commonly considered to be a random and unregulated form of cell death; however, recent studies have identified a previously unknown form of programmed necrosis called receptor-interacting protein kinase (RIPK-dependent necrosis (or necroptosis, which is controlled by the kinases RIPK1 and RIPK3. Although RIPK-dependent necrosis has been implicated in a variety of disease states, including atherosclerosis, myocardial organ damage, stroke, ischemia–reperfusion injury, pancreatitis, and inflammatory bowel disease. However its involvement in APAP-induced hepatocyte necrosis remains elusive. Here, we showed that RIPK1 phosphorylation, which is a hallmark of RIPK-dependent necrosis, was induced by APAP, and the expression pattern of RIPK1 and RIPK3 in the liver overlapped with that of CYP2E1, whose activity around the central vein area has been demonstrated to be critical for the development of APAP-induced hepatic injury. Moreover, a RIPK1 inhibitor ameliorated APAP-induced hepatotoxicity in an animal model, which was underscored by significant suppression of the release of hepatic enzymes and cytokine expression levels. RIPK1 inhibition decreased reactive oxygen species levels produced in APAP-injured hepatocytes, whereas CYP2E1 expression and the depletion rate of total glutathione were unaffected. Of note, RIPK1 inhibition also conferred resistance to oxidative stress in hepatocytes. These data collectively demonstrated a RIPK-dependent necrotic mechanism operates in the APAP-injured liver and inhibition of this pathway may be beneficial for APAP-induced fulminant hepatic failure.

  4. Use of Arctium lappa Extract Against Acetaminophen-Induced Hepatotoxicity in Rats

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    El-Kott, Attalla Farag; Bin-Meferij, Mashael Mohammed

    2015-01-01

    Background: Severe destructive hepatic injuries can be induced by acetaminophen overdose and may lead to acute hepatic failure. Objective: To investigate the ameliorative effects of Arctium lappa root extract on acetaminophen-induced hepatotoxicity. Methods: Rats were divided into 4 groups: normal control group, Arctium lappa extract group, acetaminophen-injected group, and acetaminophen treated with Arctium lappa extract group. Results: The treatment with Arctium lappa extract reduc...

  5. Effect of amlodipine, lisinopril and allopurinol on acetaminophen-induced hepatotoxicity in rats

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    Nesreen E.M. Mohammed

    2016-11-01

    Conclusion: Amlodipine, lisinopril or allopurinol can protect against acetaminophen-induced hepatotoxicity, showing mechanistic roles of calcium channels, angiotensin converting enzyme and xanthine oxidase enzyme in the pathogenesis of hepatotoxicity induced by acetaminophen.

  6. Acetaminophen-induced acute liver injury in HCV transgenic mice

    International Nuclear Information System (INIS)

    Uehara, Takeki; Kosyk, Oksana; Jeannot, Emmanuelle; Bradford, Blair U.; Tech, Katherine; Macdonald, Jeffrey M.; Boorman, Gary A.; Chatterjee, Saurabh; Mason, Ronald P.; Melnyk, Stepan B.; Tryndyak, Volodymyr P.; Pogribny, Igor P.; Rusyn, Ivan

    2013-01-01

    The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wild type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24 h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility. -- Highlights: ► Acetaminophen-induced liver injury is a significant clinical challenge. ► HCV-infected subjects may be at higher risk for acetaminophen-induced liver injury. ► We used HCV transgenics to test if liver injury due to acetaminophen is exacerbated.

  7. Acetaminophen-induced acute liver injury in HCV transgenic mice

    Energy Technology Data Exchange (ETDEWEB)

    Uehara, Takeki; Kosyk, Oksana; Jeannot, Emmanuelle; Bradford, Blair U. [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States); Tech, Katherine; Macdonald, Jeffrey M. [Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States); Boorman, Gary A. [Covance, Chantilly, VA 20151 (United States); Chatterjee, Saurabh; Mason, Ronald P. [Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, RTP, NC 27713 (United States); Melnyk, Stepan B. [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72201 (United States); Tryndyak, Volodymyr P.; Pogribny, Igor P. [Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Rusyn, Ivan, E-mail: iir@unc.edu [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States)

    2013-01-15

    The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wild type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24 h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility. -- Highlights: ► Acetaminophen-induced liver injury is a significant clinical challenge. ► HCV-infected subjects may be at higher risk for acetaminophen-induced liver injury. ► We used HCV transgenics to test if liver injury due to acetaminophen is exacerbated.

  8. Use of Arctium lappa Extract Against Acetaminophen-Induced Hepatotoxicity in Rats.

    Science.gov (United States)

    El-Kott, Attalla Farag; Bin-Meferij, Mashael Mohammed

    2015-12-01

    Severe destructive hepatic injuries can be induced by acetaminophen overdose and may lead to acute hepatic failure. To investigate the ameliorative effects of Arctium lappa root extract on acetaminophen-induced hepatotoxicity. Rats were divided into 4 groups: normal control group, Arctium lappa extract group, acetaminophen-injected group, and acetaminophen treated with Arctium lappa extract group. The treatment with Arctium lappa extract reduced serum alanine transaminase, aspartate aminotransferase, and alkaline phosphatase in the acetaminophen group when compared with the control group. DNA fragments in the acetaminophen-injected group were also significantly increased (P Arctium lappa treatment (12.97±0.89 nmol/mg) when compared with the acetaminophen-treated-only group (12.97±0.89 nmol/mg). Histopathologic examination revealed that acetaminophen administration produced hepatic cell necrosis, infiltrate of lymphocytes, and vacuolation that were associated with the acetaminophen-treated animal group, but the degree of acetaminophen-induced hepatotoxicity was mediated by treatment with Arctium lappa extract. Arctium lappa can prevent most of the hepatic tissue damage caused by acetaminophen overdose in rats.

  9. Fructose diet alleviates acetaminophen-induced hepatotoxicity in mice.

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    Cho, Sungjoon; Tripathi, Ashutosh; Chlipala, George; Green, Stefan; Lee, Hyunwoo; Chang, Eugene B; Jeong, Hyunyoung

    2017-01-01

    Acetaminophen (APAP) is a commonly used analgesic and antipyretic that can cause hepatotoxicity due to production of toxic metabolites via cytochrome P450 (Cyp) 1a2 and Cyp2e1. Previous studies have shown conflicting effects of fructose (the major component in Western diet) on the susceptibility to APAP-induced hepatotoxicity. To evaluate the role of fructose-supplemented diet in modulating the extent of APAP-induced liver injury, male C57BL/6J mice were given 30% (w/v) fructose in water (or regular water) for 8 weeks, followed by oral administration of APAP. APAP-induced liver injury (determined by serum levels of liver enzymes) was decreased by two-fold in mice pretreated with fructose. Fructose-treated mice exhibited (~1.5 fold) higher basal glutathione levels and (~2 fold) lower basal (mRNA and activity) levels of Cyp1a2 and Cyp2e1, suggesting decreased bioactivation of APAP and increased detoxification of toxic metabolite in fructose-fed mice. Hepatic mRNA expression of heat shock protein 70 was also found increased in fructose-fed mice. Analysis of bacterial 16S rRNA gene amplicons from the cecal samples of vehicle groups showed that the fructose diet altered gut bacterial community, leading to increased α-diversity. The abundance of several bacterial taxa including the genus Anaerostipes was found to be significantly correlated with the levels of hepatic Cyp2e1, Cyp1a2 mRNA, and glutathione. Together, these results suggest that the fructose-supplemented diet decreases APAP-induced liver injury in mice, in part by reducing metabolic activation of APAP and inducing detoxification of toxic metabolites, potentially through altered composition of gut microbiota.

  10. Fructose diet alleviates acetaminophen-induced hepatotoxicity in mice.

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    Sungjoon Cho

    Full Text Available Acetaminophen (APAP is a commonly used analgesic and antipyretic that can cause hepatotoxicity due to production of toxic metabolites via cytochrome P450 (Cyp 1a2 and Cyp2e1. Previous studies have shown conflicting effects of fructose (the major component in Western diet on the susceptibility to APAP-induced hepatotoxicity. To evaluate the role of fructose-supplemented diet in modulating the extent of APAP-induced liver injury, male C57BL/6J mice were given 30% (w/v fructose in water (or regular water for 8 weeks, followed by oral administration of APAP. APAP-induced liver injury (determined by serum levels of liver enzymes was decreased by two-fold in mice pretreated with fructose. Fructose-treated mice exhibited (~1.5 fold higher basal glutathione levels and (~2 fold lower basal (mRNA and activity levels of Cyp1a2 and Cyp2e1, suggesting decreased bioactivation of APAP and increased detoxification of toxic metabolite in fructose-fed mice. Hepatic mRNA expression of heat shock protein 70 was also found increased in fructose-fed mice. Analysis of bacterial 16S rRNA gene amplicons from the cecal samples of vehicle groups showed that the fructose diet altered gut bacterial community, leading to increased α-diversity. The abundance of several bacterial taxa including the genus Anaerostipes was found to be significantly correlated with the levels of hepatic Cyp2e1, Cyp1a2 mRNA, and glutathione. Together, these results suggest that the fructose-supplemented diet decreases APAP-induced liver injury in mice, in part by reducing metabolic activation of APAP and inducing detoxification of toxic metabolites, potentially through altered composition of gut microbiota.

  11. 5-Lipoxygenase Deficiency Reduces Acetaminophen-Induced Hepatotoxicity and Lethality

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    Miriam S. N. Hohmann

    2013-01-01

    Full Text Available 5-Lipoxygenase (5-LO converts arachidonic acid into leukotrienes (LTs and is involved in inflammation. At present, the participation of 5-LO in acetaminophen (APAP-induced hepatotoxicity and liver damage has not been addressed. 5-LO deficient (5-LO-/- mice and background wild type mice were challenged with APAP (0.3–6 g/kg or saline. The lethality, liver damage, neutrophil and macrophage recruitment, LTB4, cytokine production, and oxidative stress were assessed. APAP induced a dose-dependent mortality, and the dose of 3 g/kg was selected for next experiments. APAP induced LTB4 production in the liver, the primary target organ in APAP toxicity. Histopathological analysis revealed that 5-LO-/- mice presented reduced APAP-induced liver necrosis and inflammation compared with WT mice. APAP-induced lethality, increase of plasma levels of aspartate aminotransferase and alanine aminotransferase, liver cytokine (IL-1β, TNF-α, IFN-γ, and IL-10, superoxide anion, and thiobarbituric acid reactive substances production, myeloperoxidase and N-acetyl-β-D-glucosaminidase activity, Nrf2 and gp91phox mRNA expression, and decrease of reduced glutathione and antioxidant capacity measured by 2,2′-azinobis(3-ethylbenzothiazoline 6-sulfonate assay were prevented in 5-LO-/- mice compared to WT mice. Therefore, 5-LO deficiency resulted in reduced mortality due to reduced liver inflammatory and oxidative damage, suggesting 5-LO is a promising target to reduce APAP-induced lethality and liver inflammatory/oxidative damage.

  12. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity

    DEFF Research Database (Denmark)

    Schmidt, Lars E; Dalhoff, Kim

    2002-01-01

    Hypophosphatemia is frequently observed in acetaminophen-induced hepatotoxicity and may be involved in the pathogenesis of hepatic failure. The aim of the study was to evaluate the prognostic value of serial measurements of serum phosphate in patients with severe acetaminophen poisoning. Prospect......Hypophosphatemia is frequently observed in acetaminophen-induced hepatotoxicity and may be involved in the pathogenesis of hepatic failure. The aim of the study was to evaluate the prognostic value of serial measurements of serum phosphate in patients with severe acetaminophen poisoning...... Hospital (KCH) criteria. Phosphate concentrations were significantly higher in nonsurvivors than in survivors at 48 to 72 hours after overdose (mean 2.65 +/- 1.18 mmol/L vs. 0.68 +/- 0.22 mmol/L, P L vs. 0.59 +/- 0.23 mmol/L, P ...). A threshold phosphate concentration of 1.2 mmol/L at 48 to 96 hours after overdose had sensitivity 89%, specificity 100%, accuracy 98%, positive predictive value 100%, and negative predictive value 98%. The phosphate criteria had higher sensitivity, accuracy, and positive and negative predictive values than...

  13. Acetaminophen Induced Hepatotoxicity in Wistar Rats—A Proteomic Approach

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    Soundharrajan Ilavenil

    2016-01-01

    Full Text Available Understanding the mechanism of chemical toxicity, which is essential for cross-species and dose extrapolations, is a major challenge for toxicologists. Standard mechanistic studies in animals for examining the toxic and pathological changes associated with the chemical exposure have often been limited to the single end point or pathways. Toxicoproteomics represents a potential aid to the toxicologist to understand the multiple pathways involved in the mechanism of toxicity and also determine the biomarkers that are possible to predictive the toxicological response. We performed an acute toxicity study in Wistar rats with the prototype liver toxin; the acetaminophen (APAP effects on protein profiles in the liver and its correlation with the plasma biochemical markers for liver injury were analyzed. Three separate groups—control, nontoxic (150 mg/kg and toxic dose (1500 mg/kg of APAP—were studied. The proteins extracted from the liver were separated by 2-DE and analyzed by MALDI-TOF. The differential proteins in the gels were analyzed by BIORAD’s PDQuest software and identified by feeding the peptide mass fingerprint data to various public domain programs like Mascot and MS-Fit. The identified proteins in toxicity-induced rats were classified based on their putative protein functions, which are oxidative stress (31%, immunity (14%, neurological related (12% and transporter proteins (2%, whereas in non-toxic dose-induced rats they were  oxidative stress (9%, immunity (6%, neurological (14% and transporter proteins (9%. It is evident that the percentages of oxidative stress and immunity-related proteins were up-regulated in toxicity-induced rats as compared with nontoxic and control rats. Some of the liver drug metabolizing and detoxifying enzymes were depleted under toxic conditions compared with non-toxic rats. Several other proteins were identified as a first step in developing an in-house rodent liver toxicoproteomics database.

  14. Effects of α-Melanocortin Enantiomers on Acetaminophen-Induced Hepatotoxicity in CBA Mice

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    Dražen Vikić-Topić

    2009-12-01

    Full Text Available Proteins and peptides in mammals are based exclusively on L-amino acids. Recent investigations show that D-amino acids exhibit physiological effects in vivo, despite of their very small quantities. We have investigated the hepatoprotective effects of the Land D-enantiomers of α-melanocortin peptide (α-MSH. The results showed that peptideenantiomerism is related to the protective effects of melanocortin peptides in vivo. L-α-MSH exhibited potent hepatoprotective effect in the experimental model of acetaminophen induced hepatotoxicity in male CBA mice, while its D-mirror image was inefficient. Furthermore, the antibody to the L-peptide did not recognize the D-structure. The results indicate that the opposite peptide configuration may be used to modulate its function and metabolism in vivo and in vitro.

  15. Dynamic and accurate assessment of acetaminophen-induced hepatotoxicity by integrated photoacoustic imaging and mechanistic biomarkers in vivo.

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    Brillant, Nathalie; Elmasry, Mohamed; Burton, Neal C; Rodriguez, Josep Monne; Sharkey, Jack W; Fenwick, Stephen; Poptani, Harish; Kitteringham, Neil R; Goldring, Christopher E; Kipar, Anja; Park, B Kevin; Antoine, Daniel J

    2017-10-01

    The prediction and understanding of acetaminophen (APAP)-induced liver injury (APAP-ILI) and the response to therapeutic interventions is complex. This is due in part to sensitivity and specificity limitations of currently used assessment techniques. Here we sought to determine the utility of integrating translational non-invasive photoacoustic imaging of liver function with mechanistic circulating biomarkers of hepatotoxicity with histological assessment to facilitate the more accurate and precise characterization of APAP-ILI and the efficacy of therapeutic intervention. Perturbation of liver function and cellular viability was assessed in C57BL/6J male mice by Indocyanine green (ICG) clearance (Multispectral Optoacoustic Tomography (MSOT)) and by measurement of mechanistic (miR-122, HMGB1) and established (ALT, bilirubin) circulating biomarkers in response to the acetaminophen and its treatment with acetylcysteine (NAC) in vivo. We utilised a 60% partial hepatectomy model as a situation of defined hepatic functional mass loss to compared acetaminophen-induced changes to. Integration of these mechanistic markers correlated with histological features of APAP hepatotoxicity in a time-dependent manner. They accurately reflected the onset and recovery from hepatotoxicity compared to traditional biomarkers and also reported the efficacy of NAC with high sensitivity. ICG clearance kinetics correlated with histological scores for acute liver damage for APAP (i.e. 3h timepoint; r=0.90, P<0.0001) and elevations in both of the mechanistic biomarkers, miR-122 (e.g. 6h timepoint; r=0.70, P=0.005) and HMGB1 (e.g. 6h timepoint; r=0.56, P=0.04). For the first time we report the utility of this non-invasive longitudinal imaging approach to provide direct visualisation of the liver function coupled with mechanistic biomarkers, in the same animal, allowing the investigation of the toxicological and pharmacological aspects of APAP-ILI and hepatic regeneration. Copyright © 2017

  16. Nanoparticles formulation of Cuscuta chinensis prevents acetaminophen-induced hepatotoxicity in rats.

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    Yen, Feng-Lin; Wu, Tzu-Hui; Lin, Liang-Tzung; Cham, Thau-Ming; Lin, Chun-Ching

    2008-05-01

    Cuscuta chinensis is a commonly used traditional Chinese medicine to nourish the liver and kidney. Due to the poor water solubility of its major constituents such as flavonoids and lignans, its absorption upon oral administration could be limited. The purpose of the present study was to use the nanosuspension method to prepare C. chinensis nanoparticles (CN), and to compare the hepatoprotective and antioxidant effects of C. chinensis ethanolic extract (CE) and CN on acetaminophen-induced hepatotoxicity in rats. An oral dose of CE at 125 and 250 mg/kg and CN at 25 and 50mg/kg showed a significant hepatoprotective effect relatively to the same extent (P<0.05) by reducing levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. These biochemical assessments were supported by rat hepatic biopsy examinations. In addition, the antioxidant activities of CE and CN both significantly increased superoxide dismutase, catalase, glutathione peroxidase, and reduced malondialdehyde (P<0.05). Moreover, the results also indicated that the hepatoprotective and antioxidant effects of 50 mg/kg CN was effectively better than 125 mg/kg CE (P<0.05), and an oral dose of CN that is five times as less as CE could exhibit similar levels of outcomes. In conclusion, we suggest that the nanoparticles system can be applied to overcome other water poorly soluble herbal medicines and furthermore to decrease the treatment dosage.

  17. Competing Mechanistic Hypotheses of Acetaminophen-Induced Hepatotoxicity Challenged by Virtual Experiments.

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    Andrew K Smith

    2016-12-01

    Full Text Available Acetaminophen-induced liver injury in mice is a model for drug-induced liver injury in humans. A precondition for improved strategies to disrupt and/or reverse the damage is a credible explanatory mechanism for how toxicity phenomena emerge and converge to cause hepatic necrosis. The Target Phenomenon in mice is that necrosis begins adjacent to the lobule's central vein (CV and progresses outward. An explanatory mechanism remains elusive. Evidence supports that location dependent differences in NAPQI (the reactive metabolite formation within hepatic lobules (NAPQI zonation are necessary and sufficient prerequisites to account for that phenomenon. We call that the NZ-mechanism hypothesis. Challenging that hypothesis in mice is infeasible because 1 influential variables cannot be controlled, and 2 it would require sequential intracellular measurements at different lobular locations within the same mouse. Virtual hepatocytes use independently configured periportal-to-CV gradients to exhibit lobule-location dependent behaviors. Employing NZ-mechanism achieved quantitative validation targets for acetaminophen clearance and metabolism but failed to achieve the Target Phenomenon. We posited that, in order to do so, at least one additional feature must exhibit zonation by decreasing in the CV direction. We instantiated and explored two alternatives: 1 a glutathione depletion threshold diminishes in the CV direction; and 2 ability to repair mitochondrial damage diminishes in the CV direction. Inclusion of one or the other feature into NZ-mechanism failed to achieve the Target Phenomenon. However, inclusion of both features enabled successfully achieving the Target Phenomenon. The merged mechanism provides a multilevel, multiscale causal explanation of key temporal features of acetaminophen hepatotoxicity in mice. We discovered that variants of the merged mechanism provide plausible quantitative explanations for the considerable variation in 24-hour

  18. Potential Role of Activated Nonparenchymal Cells in Acetaminophen-Induced Potentiation of Hepatotoxicity

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    1991-06-14

    ALT is either being degraded or the activity is inhibited by something in the 133 media. AST activity in cocultures of NPCs and hepatocytes was... Paracetamol Hepatotoxicity: IN VITRO Studies in Isolated Mouse Hepatocytes. Toxicology Letters. 2229: 37-48. Casini, A. M., P. A. Ferrali and M...Acute Liver Necrosis Following Overdose of Paracetamol . British Medical Journal. 2: 497-499. Decker, T., M. L. Lohmann-Matthes, U. Karck, T. Peters

  19. Licochalcone A Upregulates Nrf2 Antioxidant Pathway and Thereby Alleviates Acetaminophen-Induced Hepatotoxicity

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    Hongming Lv

    2018-03-01

    Full Text Available Acetaminophen (APAP overdose-induced fatal hepatotoxicity is majorly characterized by overwhelmingly increased oxidative stress while enhanced nuclear factor-erythroid 2-related factor 2 (Nrf2 is involved in prevention of hepatotoxicity. Although Licochalcone A (Lico A upregulates Nrf2 signaling pathway against oxidative stress-triggered cell injury, whether it could protect from APAP-induced hepatotoxicity by directly inducing Nrf2 activation is still poorly elucidated. This study aims to explore the protective effect of Lico A against APAP-induced hepatotoxicity and its underlying molecular mechanisms. Our findings indicated that Lico A effectively decreased tert-butyl hydroperoxide (t-BHP- and APAP-stimulated cell apoptosis, mitochondrial dysfunction and reactive oxygen species generation and increased various anti-oxidative enzymes expression, which is largely dependent on upregulating Nrf2 nuclear translocation, reducing the Keap1 protein expression, and strengthening the antioxidant response element promoter activity. Meanwhile, Lico A dramatically protected against APAP-induced acute liver failure by lessening the lethality; alleviating histopathological liver changes; decreasing the alanine transaminase and aspartate aminotransferase levels, malondialdehyde formation, myeloperoxidase level and superoxide dismutase depletion, and increasing the GSH-to-GSSG ratio. Furthermore, Lico A not only significantly modulated apoptosis-related protein by increasing Bcl-2 expression, and decreasing Bax and caspase-3 cleavage expression, but also efficiently alleviated mitochondrial dysfunction by reducing c-jun N-terminal kinase phosphorylation and translocation, inhibiting Bax mitochondrial translocation, apoptosis-inducing factor and cytochrome c release. However, Lico A-inhibited APAP-induced the lethality, histopathological changes, hepatic apoptosis, and mitochondrial dysfunction in WT mice were evidently abrogated in Nrf2-/- mice. These

  20. Cuscuta arvensis Beyr "Dodder": In Vivo Hepatoprotective Effects Against Acetaminophen-Induced Hepatotoxicity in Rats.

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    Koca-Caliskan, Ufuk; Yilmaz, Ismet; Taslidere, Asli; Yalcin, Funda N; Aka, Ceylan; Sekeroglu, Nazim

    2018-05-02

    Cuscuta arvensis Beyr. is a parasitic plant, and commonly known as "dodder" in Europe, in the United States, and "tu si zi shu" in China. It is one of the preferred spices used in sweet and savory dishes. Also, it is used as a folk medicine for the treatment particularly of liver problems, knee pains, and physiological hepatitis, which occur notably in newborns and their mothers in the southeastern part of Turkey. The purpose of this study was to investigate the hepatoprotective effects and antioxidant activities of aqueous and methanolic extracts of C. arvensis Beyr. on acetaminophen (APAP)-induced acute hepatotoxicity in rats. The results were supported by subsequent histopathological studies. The hepatoprotective activity of both the aqueous and methanolic extracts at an oral dose of 125 and 250 mg/kg was investigated by observing the reduction levels or the activity of alkaline phosphatase, alkaline transaminase, aspartate aminotransferase, blood urine nitrogen, and total bilirubin content. In vivo antioxidant activity was determined by analyzing the serum superoxide dismutase, malondialdehyde, glutathione, and catalase levels. Chromatographic methods were used to isolate biologically active compounds from the extract, and spectroscopic methods were used for structure elucidation. Both the methanolic and aqueous extracts exerted noticable hepatoprotective and antioxidant effects supporting the folkloric usage of dodder. One of the bioactive compounds was kaempferol-3-O-rhamnoside, isolated and identified from the methanolic extract.

  1. Hepatoprotective and antioxidant effects of Cuscuta chinensis against acetaminophen-induced hepatotoxicity in rats.

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    Yen, Feng-Lin; Wu, Tzu-Hui; Lin, Liang-Tzung; Lin, Chun-Ching

    2007-04-20

    Tu-Si-Zi, the seeds of Cuscuta chinensis Lam. (Convolvulaceae), is a traditional Chinese medicine that is commonly used to nourish and improve the liver and kidney conditions in China and other Asian countries. As oxidative stress promotes the development of acetaminophen (APAP)-induced hepatotoxicity, the aim of the present study was to evaluate and compare the hepatoprotective effect and antioxidant activities of the aqueous and ethanolic extracts of C chinensis on APAP-induced hepatotoxicity in rats. The C chinensis ethanolic extract at an oral dose of both 125 and 250mg/kg showed a significant hepatoprotective effect relatively to the same extent (PCuscuta chinensis can prevent hepatic injuries from APAP-induced hepatotoxicity in rats and this is likely mediated through its antioxidant activities.

  2. The Ameliorative Effects of L-2-Oxothiazolidine-4-Carboxylate on Acetaminophen-Induced Hepatotoxicity in Mice

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    Jun Ho Shin

    2013-03-01

    Full Text Available The aim of the study was to investigate the ameliorative effects and the mechanism of action of L-2-oxothiazolidine-4-carboxylate (OTC on acetaminophen (APAP-induced hepatotoxicity in mice. Mice were randomly divided into six groups: normal control group, APAP only treated group, APAP + 25 mg/kg OTC, APAP + 50 mg/kg OTC, APAP + 100 mg/kg OTC, and APAP + 100 mg/kg N-acetylcysteine (NAC as a reference control group. OTC treatment significantly reduced serum alanine aminotransferase and aspartate aminotransferase levels in a dose dependent manner. OTC treatment was markedly increased glutathione (GSH production and glutathione peroxidase (GSH-px activity in a dose dependent manner. The contents of malondialdehyde and 4-hydroxynonenal in liver tissues were significantly decreased by administration of OTC and the inhibitory effect of OTC was similar to that of NAC. Moreover, OTC treatment on APAP-induced hepatotoxicity significantly reduced the formation of nitrotyrosin and terminal deoxynucleotidyl transferase dUTP nick end labeling positive areas of liver tissues in a dose dependent manner. Furthermore, the activity of caspase-3 in liver tissues was reduced by administration of OTC in a dose dependent manner. The ameliorative effects of OTC on APAP-induced liver damage in mice was similar to that of NAC. These results suggest that OTC has ameliorative effects on APAP-induced hepatotoxicity in mice through anti-oxidative stress and anti-apoptotic processes.

  3. Bee venom phospholipase A2 protects against acetaminophen-induced acute liver injury by modulating regulatory T cells and IL-10 in mice.

    Directory of Open Access Journals (Sweden)

    Hyunseong Kim

    Full Text Available The aim of this study was to investigate the protective effects of phospholipase A2 (PLA2 from bee venom against acetaminophen-induced hepatotoxicity through CD4+CD25+Foxp3+ T cells (Treg in mice. Acetaminophen (APAP is a widely used antipyretic and analgesic, but an acute or cumulative overdose of acetaminophen can cause severe hepatic failure. Tregs have been reported to possess protective effects in various liver diseases and kidney toxicity. We previously found that bee venom strongly increased the Treg population in splenocytes and subsequently suppressed immune disorders. More recently, we found that the effective component of bee venom is PLA2. Thus, we hypothesized that PLA2 could protect against liver injury induced by acetaminophen. To evaluate the hepatoprotective effects of PLA2, C57BL/6 mice or interleukin-10-deficient (IL-10-/- mice were injected with PLA2 once a day for five days and sacrificed 24 h (h after acetaminophen injection. The blood sera were collected 0, 6, and 24 h after acetaminophen injection for the analysis of aspartate aminotransferase (AST and alanine aminotransferase (ALT. PLA2-injected mice showed reduced levels of serum AST, ALT, proinflammatory cytokines, and nitric oxide (NO compared with the PBS-injected control mice. However, IL-10 was significantly increased in the PLA2-injected mice. These hepatic protective effects were abolished in Treg-depleted mice by antibody treatment and in IL-10-/- mice. Based on these findings, it can be concluded that the protective effects of PLA2 against acetaminophen-induced hepatotoxicity can be mediated by modulating the Treg and IL-10 production.

  4. Bee venom phospholipase A2 protects against acetaminophen-induced acute liver injury by modulating regulatory T cells and IL-10 in mice.

    Science.gov (United States)

    Kim, Hyunseong; Keum, Dong June; Kwak, Jung won; Chung, Hwan-Suck; Bae, Hyunsu

    2014-01-01

    The aim of this study was to investigate the protective effects of phospholipase A2 (PLA2) from bee venom against acetaminophen-induced hepatotoxicity through CD4+CD25+Foxp3+ T cells (Treg) in mice. Acetaminophen (APAP) is a widely used antipyretic and analgesic, but an acute or cumulative overdose of acetaminophen can cause severe hepatic failure. Tregs have been reported to possess protective effects in various liver diseases and kidney toxicity. We previously found that bee venom strongly increased the Treg population in splenocytes and subsequently suppressed immune disorders. More recently, we found that the effective component of bee venom is PLA2. Thus, we hypothesized that PLA2 could protect against liver injury induced by acetaminophen. To evaluate the hepatoprotective effects of PLA2, C57BL/6 mice or interleukin-10-deficient (IL-10-/-) mice were injected with PLA2 once a day for five days and sacrificed 24 h (h) after acetaminophen injection. The blood sera were collected 0, 6, and 24 h after acetaminophen injection for the analysis of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). PLA2-injected mice showed reduced levels of serum AST, ALT, proinflammatory cytokines, and nitric oxide (NO) compared with the PBS-injected control mice. However, IL-10 was significantly increased in the PLA2-injected mice. These hepatic protective effects were abolished in Treg-depleted mice by antibody treatment and in IL-10-/- mice. Based on these findings, it can be concluded that the protective effects of PLA2 against acetaminophen-induced hepatotoxicity can be mediated by modulating the Treg and IL-10 production.

  5. Early predictors of severe acetaminophen-induced hepatotoxicity in a paediatric population referred to a tertiary paediatric department

    DEFF Research Database (Denmark)

    Hedeland, Rikke Lindgaard; Andersen, Jesper; Askbo, Natasha Louise Friis

    2014-01-01

    -acetylcysteine treatment on hepatotoxicity and the incidence of nephrotoxicity. METHODS: We carried out a retrospective case study on 25 children aged 11-16 years with severe acetaminophen poisoning. RESULTS: Initial biochemical parameters predicted hepatotoxicity, defined as the maximum levels of the international...

  6. Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure

    Directory of Open Access Journals (Sweden)

    Howie Forbes

    2010-03-01

    Full Text Available Abstract Background The development of effective therapies for acute liver failure (ALF is limited by our knowledge of the pathophysiology of this condition, and the lack of suitable large animal models of acetaminophen toxicity. Our aim was to develop a reproducible invasively-monitored porcine model of acetaminophen-induced ALF. Method 35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased. Results Cytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein. Control pigs (n = 4 survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8 +/- 5.9 vs 59 +/- 2.0 mmHg, increased cardiac output (7.26 +/- 1.86 vs 3.30 +/- 0.40 l/min and decreased systemic vascular resistance (8.48 +/- 2.75 vs 16.2 +/- 1.76 mPa/s/m3. Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636 +/- 95 vs 301 +/- 26.9 mPa/s/m3 observed may reflect the development of respiratory distress syndrome. Liver damage was confirmed by deterioration in pH (7.23 +/- 0.05 vs 7.45 +/- 0.02 and prothrombin time (36 +/- 2 vs 8.9 +/- 0.3 seconds compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5 +/- 210 vs 42 +/- 8.14 coincided with a marked reduction in serum albumin (11.5 +/- 1.71 vs 25 +/- 1 g/dL in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2 +/- 36.5 vs 131.6 +/- 9.33 μmol/l. Liver histology revealed evidence of severe centrilobular necrosis

  7. Trifluoperazine inhibits acetaminophen-induced hepatotoxicity and hepatic reactive nitrogen formation in mice and in freshly isolated hepatocytes

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    Sudip Banerjee

    Full Text Available The hepatotoxicity of acetaminophen (APAP occurs by initial metabolism to N-acetyl-p-benzoquinone imine which depletes GSH and forms APAP-protein adducts. Subsequently, the reactive nitrogen species peroxynitrite is formed from nitric oxide (NO and superoxide leading to 3-nitrotyrosine in proteins. Toxicity occurs with inhibited mitochondrial function. We previously reported that in hepatocytes the nNOS (NOS1 inhibitor NANT inhibited APAP toxicity, reactive nitrogen and oxygen species formation, and mitochondrial dysfunction. In this work we examined the effect of trifluoperazine (TFP, a calmodulin antagonist that inhibits calcium induced nNOS activation, on APAP hepatotoxicity and reactive nitrogen formation in murine hepatocytes and in vivo. In freshly isolated hepatocytes TFP inhibited APAP induced toxicity, reactive nitrogen formation (NO, GSNO, and 3-nitrotyrosine in protein, reactive oxygen formation (superoxide, loss of mitochondrial membrane potential, decreased ATP production, decreased oxygen consumption rate, and increased NADH accumulation. TFP did not alter APAP induced GSH depletion in the hepatocytes or the formation of APAP protein adducts which indicated that reactive metabolite formation was not inhibited. Since we previously reported that TFP inhibits the hepatotoxicity of APAP in mice without altering hepatic APAP-protein adduct formation, we examined the APAP treated mouse livers for evidence of reactive nitrogen formation. 3-Nitrotyrosine in hepatic proteins and GSNO were significantly increased in APAP treated mouse livers and decreased in the livers of mice treated with APAP plus TFP. These data are consistent with a hypothesis that APAP hepatotoxicity occurs with altered calcium metabolism, activation of nNOS leading to increased reactive nitrogen formation, and mitochondrial dysfunction. Keywords: Acetaminophen, Neuronal nitric oxide, Oxidative stress, Mitochondria

  8. Efficacy of free glutathione and niosomal glutathione in the treatment of acetaminophen-induced hepatotoxicity in cats

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    L.A. Denzoin Vulcano

    2013-06-01

    Full Text Available Acetaminophen (APAP administration results in hepatotoxicity and hematotoxicity in cats. The response to three different treatments against APAP poisoning was evaluated. Free glutathione (GSH (200mg/kg, niosomal GSH (14 mg/kg and free amino acids (180 mg/kg of N-acetylcysteine and 280 mg/kg of methionine were administered to cats that were intoxicated with APAP (a single dose of 150 mg/kg, p.o.. Serum concentration of alanine aminotransferase (ALT along with serum, liver and erythrocyte concentration of GSH and methemoglobin percentage were measured before and 4, 24 and 72 hours after APAP administration. Free GSH (200 mg/kg and niosomal GSH (14 mg/kg were effective in reducing hepatotoxicity and hematotoxicity in cats intoxicated with a dose of 150 mg/kg APAP. We conclude that both types of treatments can protect the liver and haemoglobin against oxidative stress in APAP intoxicated cats. Furthermore, our results showed that treatment with niosomal GSH represents an effective therapeutic approach for APAP poisoning.

  9. Caspase-Mediated Anti-Apoptotic Effect of Ginsenoside Rg5, a Main Rare Ginsenoside, on Acetaminophen-Induced Hepatotoxicity in Mice.

    Science.gov (United States)

    Wang, Zi; Hu, Jun-Nan; Yan, Meng-Han; Xing, Jing-Jing; Liu, Wen-Cong; Li, Wei

    2017-10-25

    Frequent overdose of acetaminophen (APAP) is one of the most common and important incentives of acute hepatotoxicity. Prior to this work, our research group confirmed that black ginseng (Panax ginseng, BG) showed powerful protective effects on APAP-induced ALI. However, it is not clear which kind of individual ginsenoside from BG plays such a liver protection effect. The objective of the current investigation was to evaluate whether ginsenoside Rg5 (G-Rg5) protected against APAP-induced hepatotoxicity and the involved action mechanisms. Mice were administrated with G-Rg5 at two dosages of 10 or 20 mg/kg for 7 consecutive days. After the last treatment, all of the animals that received a single intraperitoneal injection of APAP (250 mg/kg) showed severe liver toxicity after 24 h, and the liver protection effects of G-Rg5 were examined. The results clearly indicated that pretreatment with G-Rg5 remarkably inhibited the production of serum tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) compared with the APAP group. Meanwhile, G-Rg5 decreased the hepatic malondialdehyde (MDA) content, the protein expression levels of 4-hydroxynonenal (4-HNE) and cytochrome P450 2E1 (CYP2E1) in the liver tissues. G-Rg5 decreased APAP caused the hepatic overexpression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Furthermore, analysis of immunohistochemistry and Western blotting also indicated that G-Rg5 pretreatment inhibited activation of apoptotic pathways mainly via increasing the expression of Bcl-2 protein, decreasing the expression of Bax protein, proliferating cell nuclear antigen (PCNA), cytochrome c, caspase-3, caspase-8, and caspase-9. Liver histopathological observation provided further evidence that pretreatment with G-Rg5 could significantly inhibit hepatocyte necrosis, inflammatory cell infiltration, and apoptosis caused by APAP. In conclusion, the present study clearly demonstrates that G-Rg5 exerts a liver protection effect against

  10. Hepatoprotective Effect of Opuntia robusta and Opuntia streptacantha Fruits against Acetaminophen-Induced Acute Liver Damage

    NARCIS (Netherlands)

    Gonzalez Ponce, Herson Antonio; Consolacion Martinez-Saldana, Maria; Rosa Rincon-Sanchez, Ana; Teresa Sumaya-Martinez, Maria; Buist-Homan, Manon; Faber, Klaas Nico; Moshage, Han; Jaramillo-Juarez, Fernando

    2016-01-01

    Acetaminophen (APAP)-induced acute liver failure (ALF) is a serious health problem in developed countries. N-acetyl-L-cysteine (NAC), the current therapy for APAP-induced ALF, is not always effective, and liver transplantation is often needed. Opuntia spp. fruits are an important source of nutrients

  11. Freshly isolated hepatocyte transplantation in acetaminophen-induced hepatotoxicity model in rats Transplante de hepatócitos recém-isolados em um modelo de hepatotoxicidade induzida por acetaminofeno em ratos

    Directory of Open Access Journals (Sweden)

    Daniela Rodrigues

    2012-12-01

    Full Text Available CONTEXT: Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotopic liver transplantation. OBJECTIVE: The aim of the current study was to investigate the feasibility of freshly isolated rat hepatocyte transplantation in acetaminophen-induced hepatotoxicity model. METHODS: Hepatocytes were isolated from male Wistar rats and transplanted 24 hours after acetaminophen administration in female recipients. Female rats received either 1x10(7 hepatocytes or phosphate buffered saline through the portal vein or into the spleen and were sacrificed after 48 hours. RESULTS: Alanine aminotransferase levels measured within the experiment did not differ between groups at any time point. Molecular analysis and histology showed presence of hepatocytes in liver of transplanted animals injected either through portal vein or spleen. CONCLUSION: These data demonstrate the feasibility and efficacy of hepatocyte transplantation in the liver or spleen in a mild acetaminophen-induced hepatotoxicity model.CONTEXTO: O transplante de hepatócitos é uma modalidade terapêutica atrativa para doenças hepáticas como alternativa ao transplante hepático ortotópico. OBJETIVO: Investigar a factibilidade do uso de hepatócitos frescos isolados de ratos em um modelo de hepatotoxicidade induzida por paracetamol. MÉTODOS: Hepatócitos foram isolados de ratos Wistar machos e transplantados 24 horas após a administração de paracetamol em receptores fêmeas. As ratas receberam 1x10(7 hepatócitos ou tampão salina fosfato pela veia porta ou no baço e foram sacrificadas após 48 horas. RESULTADOS: Os níveis de alanina aminotransferase medidos durante o experimento não diferiram entre os grupos em nenhum momento. Análises moleculares e histológicas demonstraram a presença de hepatócitos no fígado dos animais transplantados pelo baço ou pela veia porta. CONCLUSÃO: Os dados indicam a factibilidade e eficácia do

  12. Hepatoprotective Effect of Opuntia robusta and Opuntia streptacantha Fruits against Acetaminophen-Induced Acute Liver Damage

    Directory of Open Access Journals (Sweden)

    Herson Antonio González-Ponce

    2016-10-01

    Full Text Available Acetaminophen (APAP-induced acute liver failure (ALF is a serious health problem in developed countries. N-acetyl-L-cysteine (NAC, the current therapy for APAP-induced ALF, is not always effective, and liver transplantation is often needed. Opuntia spp. fruits are an important source of nutrients and contain high levels of bioactive compounds, including antioxidants. The aim of this study was to evaluate the hepatoprotective effect of Opuntia robusta and Opuntia streptacantha extracts against APAP-induced ALF. In addition, we analyzed the antioxidant activities of these extracts. Fruit extracts (800mg/kg/day, orally were given prophylactically to male Wistar rats before intoxication with APAP (500 mg/kg, intraperitoneally. Rat hepatocyte cultures were exposed to 20mmol/LAPAP, and necrosis was assessed by LDH leakage. Opuntia robusta had significantly higher levels of antioxidants than Opuntia streptacantha. Both extracts significantly attenuated APAP-induced injury markers AST, ALT and ALP and improved liver histology. The Opuntia extracts reversed APAP-induced depletion of liver GSH and glycogen stores. In cultured hepatocytes, Opuntia extracts significantly reduced leakage of LDH and cell necrosis, both prophylactically and therapeutically. Both extracts appeared to be superior to NAC when used therapeutically. We conclude that Opuntia extracts are hepatoprotective and can be used as a nutraceutical to prevent ALF.

  13. Short day photoperiod protects against acetaminophen-induced ...

    African Journals Online (AJOL)

    Prof. Ogunji

    blood was collected by cardiac puncture for the estimation of liver enzymes activities. Liver ... revealed the protective effects of short photoperiod against acetaminophen-induced hepatotoxicity and lipid .... homogenized in ice cold KCl (100mM) containing. 0.003M ... This was followed by the addition of 1.0ml water and 5.0ml ...

  14. 20(R)-ginsenoside Rg3, a rare saponin from red ginseng, ameliorates acetaminophen-induced hepatotoxicity by suppressing PI3K/AKT pathway-mediated inflammation and apoptosis.

    Science.gov (United States)

    Zhou, Yan-Dan; Hou, Jin-Gang; Liu, Wei; Ren, Shen; Wang, Ying-Ping; Zhang, Rui; Chen, Chen; Wang, Zi; Li, Wei

    2018-06-01

    Although ginsenoside Rg3 was isolated as a major component of Korea red ginseng and confirmed to exert potential hepatoprotective effect on acetaminophen (APAP)-induced liver injury via induction of glutathione S-transferase (GST) in vitro, thein vivo hepatoprotective effect of Rg3 and the underlying molecular mechanism of action remain unclear. The current study was aimed to explore whether 20(R)-Ginsenoside Rg3 (20(R)-Rg3) could alleviate acetaminophen-induced liver injury in mice and to determine the involvement of PI3K/AKT signaling pathway. Our findings demonstrated that a single injection of APAP (250 mg/kg) increased the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β); such increases were attenuated by pretreatment of mice with 20(R)-Rg3 for seven days. The depletion of glutathione (GSH), generation of malondialdehyde (MDA) and the over expression of cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) caused by APAP exposure were also inhibited by 20(R)-Rg3 pretreatment. Moreover, 20(R)-Rg3 pretreatment significantly alleviated APAP-induced apoptosis, necrosis, and inflammatory infiltration in liver tissues. Importantly, 20(R)-Rg3 effectively attenuated APAP-induced liver injury in part via activating PI3K/AKT signaling pathway. In summary, 20(R)-Rg3 exerted liver protection against APAP-caused hepatotoxicity evidenced by inhibition of oxidative stress and inflammatory response, alleviation of hepatocellular necrosis and apoptosis via activation of PI3K/AKT signaling pathway, showing potential as a novel therapeutic agent to prevent liver damage. Copyright © 2018 Elsevier B.V. All rights reserved.

  15. Induction of Mkp-1 and Nuclear Translocation of Nrf2 by Limonoids from Khaya grandifoliola C.DC Protect L-02 Hepatocytes against Acetaminophen-Induced Hepatotoxicity

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    Arnaud F. Kouam

    2017-09-01

    Full Text Available Drug-induced liver injury (DILI is a major clinical problem where natural compounds hold promise for its abrogation. Khaya grandifoliola (Meliaceae is used in Cameroonian traditional medicine for the treatment of liver related diseases and has been studied for its hepatoprotective properties. Till date, reports showing the hepatoprotective molecular mechanism of the plant are lacking. The aim of this study was therefore to identify compounds from the plant bearing hepatoprotective activity and the related molecular mechanism by assessing their effects against acetaminophen (APAP-induced hepatotoxicity in normal human liver L-02 cells line. The cells were exposed to APAP (10 mM or co-treated with phytochemical compounds (40 μM over a period of 36 h and, biochemical and molecular parameters assessed. Three known limonoids namely 17-epi-methyl-6-hydroxylangolensate, 7-deacetoxy-7-oxogedunin and deacetoxy-7R-hydroxygedunin were identified. The results of cells viability and membrane integrity, reactive oxygen species generation and lipid membrane peroxidation assays, cellular glutathione content determination as well as expression of cytochrome P450 2E1 demonstrated the protective action of the limonoids. Immunoblotting analysis revealed that limonoids inhibited APAP-induced c-Jun N-terminal Kinase phosphorylation (p-JNK, mitochondrial translocation of p-JNK and Bcl2-associated X Protein, and the release of Apoptosis-inducing Factor into the cytosol. Interestingly, limonoids increased the expression of Mitogen-activated Protein Kinase Phosphatase (Mkp-1, an endogenous inhibitor of JNK phosphorylation and, induced the nuclear translocation of Nuclear Factor Erythroid 2-related Factor-2 (Nrf2 and decreased the expression of Kelch-like ECH-associated Protein-1. The limonoids also reversed the APAP-induced decreased mRNA levels of Catalase, Superoxide Dismutase-1, Glutathione-S-Transferase and Methionine Adenosyltransferase-1A. The obtained results

  16. Phytoextract of Indian mustard seeds acts by suppressing the generation of ROS against acetaminophen-induced hepatotoxicity in HepG2 cells.

    Science.gov (United States)

    Parikh, Harita; Pandita, Nancy; Khanna, Aparna

    2015-07-01

    Indian mustard [Brassica juncea (L.) Czern. & Coss. (Brassicaceae)] is reported to possess diverse pharmacological properties. However, limited information is available concerning its hepatoprotective activity and mechanism of action. To study the protective mechanism of mustard seed extract against acetaminophen (APAP) toxicity in a hepatocellular carcinoma (HepG2) cell line. Hepatotoxicity models were established using APAP (2.5-22.5 mM) based on the cytotoxicity profile. An antioxidant-rich fraction from mustard seeds was extracted and evaluated for its hepatoprotective potential. The mechanism of action was elucidated using various in vitro antioxidant assays, the detection of intracellular generation of reactive oxygen species (ROS), and cell cycle analysis. The phytoconstituents isolated via HPLC-DAD were also evaluated for hepatoprotective activity. Hydromethanolic seed extract exhibited hepatoprotective activity in post- and pre-treatment models of 20 mM APAP toxicity and restored the elevated levels of liver indices to normal values (p DAD analysis revealed the presence quercetin, vitamin E, and catechin, which exhibited hepatoprotective activity. A phytoextract of mustard seeds acts by suppressing the generation of ROS in response to APAP toxicity.

  17. Protective Effects of Tormentic Acid, a Major Component of Suspension Cultures of Eriobotrya japonica Cells, on Acetaminophen-Induced Hepatotoxicity in Mice

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    Wen-Ping Jiang

    2017-05-01

    Full Text Available An acetaminophen (APAP overdose can cause hepatotoxicity and lead to fatal liver damage. The hepatoprotective effects of tormentic acid (TA on acetaminophen (APAP-induced liver damage were investigated in mice. TA was intraperitoneally (i.p. administered for six days prior to APAP administration. Pretreatment with TA prevented the elevation of serum aspartate aminotransferase (AST, alanine aminotransferase (ALT, total bilirubin (T-Bil, total cholesterol (TC, triacylglycerol (TG, and liver lipid peroxide levels in APAP-treated mice and markedly reduced APAP-induced histological alterations in liver tissues. Additionally, TA attenuated the APAP-induced production of nitric oxide (NO, reactive oxygen species (ROS, tumor necrosis factor-alpha (TNF-α, interleukin-1beta (IL-1β, and IL-6. Furthermore, the Western blot analysis showed that TA blocked the protein expression of inducible NO synthase (iNOS and cyclooxygenase-2 (COX-2, as well as the inhibition of nuclear factor-kappa B (NF-κB and mitogen-activated protein kinases (MAPKs activation in APAP-injured liver tissues. TA also retained the superoxidase dismutase (SOD, glutathione peroxidase (GPx, and catalase (CAT in the liver. These results suggest that the hepatoprotective effects of TA may be related to its anti-inflammatory effect by decreasing thiobarbituric acid reactive substances (TBARS, iNOS, COX-2, TNF-α, IL-1β, and IL-6, and inhibiting NF-κB and MAPK activation. Antioxidative properties were also observed, as shown by heme oxygenase-1 (HO-1 induction in the liver, and decreases in lipid peroxides and ROS. Therefore, TA may be a potential therapeutic candidate for the prevention of APAP-induced liver injury by inhibiting oxidative stress and inflammation.

  18. Identification of Novel Translational Urinary Biomarkers for Acetaminophen-Induced Acute Liver Injury Using Proteomic Profiling in Mice

    NARCIS (Netherlands)

    van Swelm, Rachel P. L.; Laarakkers, Coby M. M.; van der Kuur, Ellen C.; Morava-Kozicz, Eva; Wevers, Ron A.; Augustijn, Kevin D.; Touw, Daan J.; Sandel, Maro H.; Masereeuw, Rosalinde; Russel, Frans G. M.

    2012-01-01

    Drug-induced liver injury (DILI) is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced

  19. Serum neopterin and soluble CD163 as markers of macrophage activation in paracetamol (acetaminophen)-induced human acute liver injury.

    Science.gov (United States)

    Craig, D G; Lee, P; Pryde, E A; Hayes, P C; Simpson, K J

    2013-12-01

    Macrophage activation is implicated in the pathogenesis of the systemic inflammatory response syndrome (SIRS) following paracetamol (acetaminophen) overdose (POD). Neopterin is synthesised from macrophages and reflects the intensity of monocyte/macrophage activation. Soluble CD163 (sCD163) is a marker of alternatively activated M2 macrophages. To examine neopterin and sCD163 levels in a cohort of acute liver injury patients. Consecutive patients (n = 41, (18 (43.9%) male) with acute liver injury were enrolled. Neopterin and sCD163 levels were measured by ELISA. A total of 24/33 (72.7%) POD patients developed hepatic encephalopathy (HE), and therefore acute liver failure. Both neopterin and sCD163 levels were significantly higher in PODs compared with chronic liver disease (neopterin P paracetamol overdose, and reflect the degree of macrophage activation in this condition. Serum neopterin in particular may have value as an early proxy marker of macrophage activation following paracetamol overdose. © 2013 John Wiley & Sons Ltd.

  20. Activation of p62-keap1-Nrf2 antioxidant pathway in the early stage of acetaminophen-induced acute liver injury in mice.

    Science.gov (United States)

    Shen, Zhenyu; Wang, Yu; Su, Zhenhui; Kou, Ruirui; Xie, Keqin; Song, Fuyong

    2018-02-25

    Acetaminophen (APAP) overdose can cause severe liver failure even death. Nearly half of drug-induced liver injury is attributed to APAP in the US and many European countries. Oxidative stress has been validated as a critical event involved in APAP-induced liver failure. p62/SQSTM1, a selective autophagy adaptor protein, is reported to regulate Nrf2-ARE antioxidant pathway in response to oxidative stress. However, the exact role of p62-keap1-Nrf2 antioxidant pathway in APAP-induced hepatotoxicity remains unknown. In the present study, the dose-response and time-course model in C57/BL6 mice were established by intraperitoneal injection of APAP. The results of serum alanine/aspartate aminotransferases (ALT/AST) and histological examination demonstrated that APAP overdose resulted in the severe liver injury. In the meantime, the levels of p62, phospho-p62 and nuclear Nrf2 were significantly increased by APAP in mice liver, suggesting an activation of p62-keap1-Nrf2 pathway. In addition, the expression of GSTA1 mRNA was increased in a dose-dependent manner, while the mRNA levels of HO-1 and GCLC were decreased with the increase of APAP dose. Our further investigation found that expression of HO-1 and GCLC peaked at 3 h∼6 h, and then were decreased gradually. Taken together, these results indicated that p62-keap1-Nrf2 antioxidant pathway was primarily activated in the early stage of APAP hepatotoxicity, which might play a protective role in the process of APAP-induced acute liver injury. Copyright © 2018 Elsevier B.V. All rights reserved.

  1. Curative Effects of Thiacremonone against Acetaminophen-Induced Acute Hepatic Failure via Inhibition of Proinflammatory Cytokines Production and Infiltration of Cytotoxic Immune Cells and Kupffer Cells

    Directory of Open Access Journals (Sweden)

    Yu Ri Kim

    2013-01-01

    Full Text Available High doses of acetaminophen (APAP; N-acetyl-p-aminophenol cause severe hepatotoxicity after metabolic activation by cytochrome P450 2E1. This study was undertaken to examine the preventive effects of thiacremonone, a compound extracted from garlic, on APAP-induced acute hepatic failure in male C57BL/6J. Mice received with 500 mg/kg APAP after a 7-day pretreatment with thiacremonone (10–50 mg/kg. Thiacremonone inhibited the APAP-induced serum ALT and AST levels in a dose-dependent manner, and markedly reduced the restricted area of necrosis and inflammation by administration of APAP. Thiacremonone also inhibited the APAP-induced depletion of intracellular GSH, induction of nitric oxide, and lipid peroxidation as well as expression of P450 2E1. After APAP injection, the numbers of Kupffer cells, natural killer cells, and cytotoxic T cells were elevated, but the elevated cell numbers in the liver were reduced in thiacremonone pretreated mice. The expression levels of I-309, M-CSF, MIG, MIP-1α, MIP-1β, IL-7, and IL-17 were increased by APAP treatment, which were inhibited in thiacremonone pretreated mice. These data indicate that thiacremonone could be a useful agent for the treatment of drug-induced hepatic failure and that the reduction of cytotoxic immune cells as well as proinflammatory cytokine production may be critical for the prevention of APAP-induced acute liver toxicity.

  2. Hepatotoxicity During Maintenance Therapy and Prognosis in Children With Acute Lymphoblastic Leukemia

    DEFF Research Database (Denmark)

    Ebbesen, Maria S.; Nygaard, Ulrikka; Rosthøj, Susanne

    2017-01-01

    Hepatotoxicity is a known toxicity to treatment of childhood acute lymphoblastic leukemia. Hepatotoxicity occurs during maintenance therapy and is caused by metabolites of 6-Mercaptopurine (6 MP) and Methotrexate (MTX). Our objective was to investigate the association between alanine...

  3. Experimental models of hepatotoxicity related to acute liver failure

    Energy Technology Data Exchange (ETDEWEB)

    Maes, Michaël [Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels (Belgium); Vinken, Mathieu, E-mail: mvinken@vub.ac.be [Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels (Belgium); Jaeschke, Hartmut [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City (United States)

    2016-01-01

    Acute liver failure can be the consequence of various etiologies, with most cases arising from drug-induced hepatotoxicity in Western countries. Despite advances in this field, the management of acute liver failure continues to be one of the most challenging problems in clinical medicine. The availability of adequate experimental models is of crucial importance to provide a better understanding of this condition and to allow identification of novel drug targets, testing the efficacy of new therapeutic interventions and acting as models for assessing mechanisms of toxicity. Experimental models of hepatotoxicity related to acute liver failure rely on surgical procedures, chemical exposure or viral infection. Each of these models has a number of strengths and weaknesses. This paper specifically reviews commonly used chemical in vivo and in vitro models of hepatotoxicity associated with acute liver failure. - Highlights: • The murine APAP model is very close to what is observed in patients. • The Gal/ET model is useful to study TNFα-mediated apoptotic signaling mechanisms. • Fas receptor activation is an effective model of apoptosis and secondary necrosis. • The ConA model is a relevant model of auto-immune hepatitis and viral hepatitis. • Multiple time point evaluation needed in experimental models of acute liver injury.

  4. Hepatoprotective Effects of Met-enkephalin on Acetaminophen-Induced Liver Lesions in Male CBA Mice

    OpenAIRE

    Martinić, Roko; Šošić, Hrvoje; Turčić, Petra; Konjevoda, Paško; Fučić, Aleksandra; Stojković, Ranko; Aralica, Gorana; Gabričević, Mario; Weitner, Tin; Štambuk, Nikola

    2014-01-01

    Recent histopathological investigations in patients with hepatitis suggested possible involvement of Met-enkephalin and its receptors in the pathophysiology of hepatitis. Consequently, we evaluated the potential hepatoprotective effects of this endogenous opioid pentapeptide in the experimental model of acetaminophen induced hepatotoxicity in male CBA mice. Met-enkephalin exhibited strong hepatoprotective effects in a dose of 7.5 mg/kg, which corresponds to the protective dose reported for se...

  5. Protective effect of zinc aspartate against acetaminophen induced hepato-renal toxicity in albino rats

    International Nuclear Information System (INIS)

    Mohamed, E.T.; Said, A.I.; El-Sayed, S.A.

    2011-01-01

    Zinc is an essential nutrient that is required in humans and animals for many physiological functions, including antioxidant functions. The evidence to date indicates that zinc is an important element that links antioxidant system and tissue damage. Acetaminophen (AP), a widely used analgesic and antipyretic, produces hepatocyte and renal tubular necrosis in human and animals following overdose. In human, AP is one of the most common causes of acute liver failure as a result of accidental or deliberate overdose. Moreover, the initial event in AP toxicity is a toxic metabolic injury with the release of free radicals and subsequent cellular death by necrosis and apoptosis. This study was designed to evaluate the potential protective role of zinc aspartate in case of acetaminophen induced hepato-renal toxicity in rats. A total number of 32 adult male albino rats were divided into 4 equal groups: group I (control group), group II (zinc aspartate treated group), group III (acetaminophen treated group; by a single oral dose of 750 mg/kg body weight) and group IV acetaminophen plus zinc treated group; (zinc aspartate was intraperitoneally given one hour after acetaminophen administration in a dose of 30 mg/kg body weight). Serum levels of: alanine aminotransferase, aspartate aminotransferase, direct bilirubin, blood urea nitrogen, creatinine, uric acid, xanthine oxidase (XO), glutathione (GSH), malonaldehyde (MDA) and nitric oxide (NO) were assessed in all groups. The results of this study showed that treatment with acetaminophen alone (group III) produced a significant increase in serum levels of the liver enzymes and direct bilirubin. Moreover, in the same group there was a significant increase in the blood urea nitrogen and serum creatinine compared to the control group. In addition, there was a significant increase in XO and MDA and a significant decrease in GSH and NO level. Injection of rats with zinc aspartate after acetaminophen treatment could produce a

  6. Association between consumption of Herbalife nutritional supplements and acute hepatotoxicity.

    Science.gov (United States)

    Elinav, Eran; Pinsker, Galia; Safadi, Rifaat; Pappo, Orit; Bromberg, Michal; Anis, Emilia; Keinan-Boker, Lital; Broide, Efrat; Ackerman, Zvi; Kaluski, Dorit Nitzan; Lev, Boaz; Shouval, Daniel

    2007-10-01

    Nutritional supplements are frequently considered to be harmless but indiscriminate use of unlabelled ingredients may lead to significant adverse reactions. In 2004, identification of four index cases of acute hepatitis associated with Herbalife intake led to a ministry of health investigation in all Israeli hospitals. Twelve patients with acute idiopathic liver injury in association with consumption of Herbalife products were investigated. Eleven of the patients were females, aged 49.5+/-13.4 y. One patient had stage I primary biliary cirrhosis and another had hepatitis B. Acute liver injury was diagnosed after 11.9+/-11.1 months of initiation of Herbalife consumption. Liver biopsies demonstrated active hepatitis, portal inflammation rich with eosinophils, ductular reaction and parenchymal inflammation with peri-central accentuation. One patient developed sub-fulminant and two fulminant episodes of hepatic failure. Hepatitis resolved in eleven patients, while one patient succumbed to complications following liver transplantation. Three patients resumed consumption of Herbalife products following normalization of liver enzymes, resulting in a second bout of hepatitis. An association between intake of Herbalife products and acute hepatitis was identified in Israel. We call for prospective evaluation of Herbalife products for possible hepatotoxicity. Until then, caution should be exercised by consumers, especially among individuals suffering from underlying liver disease.

  7. Silymarin prevents acetaminophen-induced hepatotoxicity in mice.

    Directory of Open Access Journals (Sweden)

    Zuzana Papackova

    Full Text Available Acetaminophen or paracetamol (APAP overdose is a common cause of liver injury. Silymarin (SLM is a hepatoprotective agent widely used for treating liver injury of different origin. In order to evaluate the possible beneficial effects of SLM, Balb/c mice were pretreated with SLM (100 mg/kg b.wt. per os once daily for three days. Two hours after the last SLM dose, the mice were administered APAP (300 mg/kg b.wt. i.p. and killed 6 (T6, 12 (T12 and 24 (T24 hours later. SLM-treated mice exhibited a significant reduction in APAP-induced liver injury, assessed according to AST and ALT release and histological examination. SLM treatment significantly reduced superoxide production, as indicated by lower GSSG content, lower HO-1 induction, alleviated nitrosative stress, decreased p-JNK activation and direct measurement of mitochondrial superoxide production in vitro. SLM did not affect the APAP-induced decrease in CYP2E1 activity and expression during the first 12 hrs. Neutrophil infiltration and enhanced expression of inflammatory markers were first detected at T12 in both groups. Inflammation progressed in the APAP group at T24 but became attenuated in SLM-treated animals. Histological examination suggests that necrosis the dominant cell death pathway in APAP intoxication, which is partially preventable by SLM pretreatment. We demonstrate that SLM significantly protects against APAP-induced liver damage through the scavenger activity of SLM and the reduction of superoxide and peroxynitrite content. Neutrophil-induced damage is probably secondary to necrosis development.

  8. Hepatoprotective activity of Tribulus terrestris extract against acetaminophen-induced toxicity in a freshwater fish (Oreochromis mossambicus).

    Science.gov (United States)

    Kavitha, P; Ramesh, R; Bupesh, G; Stalin, A; Subramanian, P

    2011-12-01

    The potential protective role of Tribulus terrestris in acetaminophen-induced hepatotoxicity in Oreochromis mossambicus was investigated. The effect of oral exposure of acetaminophen (500 mg/kg) in O. mossambicus at 24-h duration was evaluated. The plant extract (250 mg/kg) showed a remarkable hepatoprotective activity against acetaminophen-induced hepatotoxicity. It was judged from the tissue-damaging level and antioxidant levels in liver, gill, muscle and kidney tissues. Further acetaminophen impact induced a significant rise in the tissue-damaging level, and the antioxidant level was discernible from the enzyme activity modulations such as glutamate oxaloacetic transaminase, glutamate pyruvic transaminase, alkaline phosphatase, acid phosphatase, glucose-6-phosphate dehydrogenase, lactate dehydrogenase, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, lipid peroxidase and reduced glutathione. The levels of all these enzymes have significantly (p terrestris extract (250 kg/mg). Histopathological changes of liver, gill and muscle samples were compared with respective controls. The results of the present study specify the hepatoprotective and antioxidant properties of T. terrestris against acetaminophen-induced toxicity in freshwater fish, O. mossambicus.

  9. Hepatoprotective Effects of Met-enkephalin on Acetaminophen-Induced Liver Lesions in Male CBA Mice

    Directory of Open Access Journals (Sweden)

    Roko Martinić

    2014-08-01

    Full Text Available Recent histopathological investigations in patients with hepatitis suggested possible involvement of Met-enkephalin and its receptors in the pathophysiology of hepatitis. Consequently, we evaluated the potential hepatoprotective effects of this endogenous opioid pentapeptide in the experimental model of acetaminophen induced hepatotoxicity in male CBA mice. Met-enkephalin exhibited strong hepatoprotective effects in a dose of 7.5 mg/kg, which corresponds to the protective dose reported for several different animal disease models. In this group plasma alanine aminotransferase and aspartate aminotransferase enzyme activities, as well as liver necrosis score were significantly reduced in comparison to control animals treated with physiological saline (p > 0.01. The specificity of the peptide hepatoprotection was investigated from the standpoint of the receptor and peptide blockade. It was concluded that Met-enkephalin effects on the liver were mediated via δ and ζ opioid receptors. Genotoxic testing of Met-enkephalin confirmed the safety of the peptide.

  10. Synergistic protective effect of picrorhiza with honey in acetaminophen induced hepatic injury.

    Science.gov (United States)

    Gupta, Prashant; Tripathi, Alok; Agrawal, Tripti; Narayan, Chandradeo; Singh, B M; Kumar, Mohan; Kumar, Arvind

    2016-08-01

    Rhizome of picrorhiza along with honey prevents hepatic damage and cure the acetaminophen (paracetamol) induced hepatotoxicity by modulating the activity of hepatic enzymes. Here, we studied the in vivo effects of Picrorhiza kurroa and honey on acetaminophen induced hepatotoxicity Balb/c mice model. Hepatic histopathological observations of acetaminophen fed (day-6) group showed more congestion, hemorrhage, necrosis, distorted hepatic architecture and nuclear inclusion. Such damages were recompensed to normal by picrorhiza or honey alone or both in combinations. We observed increased activity of SGPT and SGOT in injured liver tissues, and that too was compensated to normal with picrorhiza or honey alone or both in combinations. We observed 1.27 and 1.23-fold enhanced activity of SGPT in serum and liver lysate, respectively while SGOT showed 1.66 and 1.11 fold enhanced activity. These two enzymes are signature enzymes of liver damage. Thus, our results support that honey may be used with drug picrorhiza due to its synergistic role to enhance hepatoprotective and hepatoregenerative ability along with allopathic drugs to mitigate the hepatotoxic effects.

  11. Replicative stress and alterations in cell cycle checkpoint controls following acetaminophen hepatotoxicity restrict liver regeneration.

    Science.gov (United States)

    Viswanathan, Preeti; Sharma, Yogeshwar; Gupta, Priya; Gupta, Sanjeev

    2018-03-05

    Acetaminophen hepatotoxicity is a leading cause of hepatic failure with impairments in liver regeneration producing significant mortality. Multiple intracellular events, including oxidative stress, mitochondrial damage, inflammation, etc., signify acetaminophen toxicity, although how these may alter cell cycle controls has been unknown and was studied for its significance in liver regeneration. Assays were performed in HuH-7 human hepatocellular carcinoma cells, primary human hepatocytes and tissue samples from people with acetaminophen-induced acute liver failure. Cellular oxidative stress, DNA damage and cell proliferation events were investigated by mitochondrial membrane potential assays, flow cytometry, fluorescence staining, comet assays and spotted arrays for protein expression after acetaminophen exposures. In experimental groups with acetaminophen toxicity, impaired mitochondrial viability and substantial DNA damage were observed with rapid loss of cells in S and G2/M and cell cycle restrictions or even exit in the remainder. This resulted from altered expression of the DNA damage regulator, ATM and downstream transducers, which imposed G1/S checkpoint arrest, delayed entry into S and restricted G2 transit. Tissues from people with acute liver failure confirmed hepatic DNA damage and cell cycle-related lesions, including restrictions of hepatocytes in aneuploid states. Remarkably, treatment of cells with a cytoprotective cytokine reversed acetaminophen-induced restrictions to restore cycling. Cell cycle lesions following mitochondrial and DNA damage led to failure of hepatic regeneration in acetaminophen toxicity but their reversibility offers molecular targets for treating acute liver failure. © 2018 John Wiley & Sons Ltd.

  12. PROTECTIVE EFFECT OF MORINGA PEREGRINA LEAVES EXTRACT ON ACETAMINOPHEN -INDUCED LIVER TOXICITY IN ALBINO RATS.

    Science.gov (United States)

    Azim, Samy Abdelfatah Abdel; Abdelrahem, Mohamed Taha; Said, Mostafa Mohamed; Khattab, Alshaimaa

    2017-01-01

    Acetaminophen is a common antipyretic drug but at overdose can cause severe hepatotoxicity that may further develop into liver failure and hepatic centrilobular necrosis in experimental animals and humans. This study was undertaken to assess the ameliorative role of Moringa peregrina leaves extract against acetaminophen toxicity in rats. Induction of hepatotoxicity was done by chronic oral administration of acetaminophen (750 mg/kg bwt) for 4 weeks. To study the possible hepatoprotective effect, Moringa peregrina leaves extract (200 mg/kg bwt) or Silymarin (50 mg/kg bwt) was administered orally, for 4 weeks, along with acetaminophen. acetaminophen significantly increased serum liver enzymes and caused oxidative stress, evidenced by significantly increased tissue malondialdehyde, glutathione peroxidase, hepatic DNA fragmentation, and significant decrease of glutathione and antioxidant enzymes in liver, blood and brain. On the other hand, administration of Moringa peregrina leaves extract reversed acetaminophen-related toxic effects through: powerful malondialdehyde suppression, glutathione peroxidase normalization and stimulation of the cellular antioxidants synthesis represented by significant increase of glutathione, catalase and superoxide dismutase in liver, blood and brain, besides, DNA fragmentation was significantly decreased in the liver tissue. acetaminophen induced oxidative damage can be improved by Moringa peregrina leaves extract-treatment, due to its antioxidant potential.

  13. Ethanol extract from portulaca oleracea L. attenuated acetaminophen-induced mice liver injury

    Science.gov (United States)

    Liu, Xue-Feng; Zheng, Cheng-Gang; Shi, Hong-Guang; Tang, Gu-Sheng; Wang, Wan-Yin; Zhou, Juan; Dong, Li-Wei

    2015-01-01

    Acetaminophen-induced liver injury represents the most frequent cause of drug-induced liver failure in the world. Portulaca oleracea L., a widely distributed weed, has been used as a folk medicine in many countries. Previously, we reported that the ethanol extracts of Portulaca oleracea L. (PO) exhibited significant anti-hypoxic activity. In the present study, we investigated the role of PO on acetaminophen (APAP) induced hepatotoxicity. The results demonstrated that PO was an effective anti-oxidative agent, which could, to some extent, reverse APAP-induced hepatotoxicity by regulating the reactive oxygen species (ROS) in the liver of mice. At the same time, PO treatment significantly decreased mice serum levels of IL-6 and TNFα and their mRNA expression in liver tissue IL-α and TNFα play an important role during APAP-induced liver injury. Furthermore, PO inhibited APAP and TNFα-induced activation of JNK, whose activation play an important effect during APAP induced liver injury. These findings suggested that administration of PO may be an effective strategy to prevent or treat liver injury induced by APAP. PMID:25901199

  14. Improved Hepatoprotective Effect of Liposome-Encapsulated Astaxanthin in Lipopolysaccharide-Induced Acute Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Chun-Hung Chiu

    2016-07-01

    Full Text Available Lipopolysaccharide (LPS-induced acute hepatotoxicity is significantly associated with oxidative stress. Astaxanthin (AST, a xanthophyll carotenoid, is well known for its potent antioxidant capacity. However, its drawbacks of poor aqueous solubility and low bioavailability have limited its utility. Liposome encapsulation is considered as an effective alternative use for the improvement of bioavailability of the hydrophobic compound. We hypothesized that AST encapsulated within liposomes (LA apparently shows improved stability and transportability compared to that of free AST. To investigate whether LA administration can efficiently prevent the LPS-induced acute hepatotoxicity, male Sprague-Dawley rats (n = six per group were orally administered liposome-encapsulated AST at 2, 5 or 10 mg/kg-day (LA-2, LA-5, and LA-10 for seven days and then were LPS-challenged (i.p., 5 mg/kg. The LA-10 administered group, but not the other groups, exhibited a significant amelioration of serum glutamic pyruvic transaminase (GPT, glutamic oxaloacetic transaminase (GOT, blood urea nitrogen (BUN, creatinine (CRE, hepatic malondialdehyde (MDA and glutathione peroxidase (GSH-Px, IL-6, and hepatic nuclear NF-κB and inducible nitric oxide synthase (iNOS, suggesting that LA at a 10 mg/kg-day dosage renders hepatoprotective effects. Moreover, the protective effects were even superior to that of positive control N-acetylcysteine (NAC, 200 mg/kg-day. Histopathologically, NAC, free AST, LA-2 and LA-5 partially, but LA-10 completely, alleviated the acute inflammatory status. These results indicate that hydrophobic AST after being properly encapsulated by liposomes improves bioavailability and can also function as potential drug delivery system in treating hepatotoxicity.

  15. Overdose pattern and outcome in paracetamol-induced acute severe hepatotoxicity

    Science.gov (United States)

    Craig, Darren G N; Bates, Caroline M; Davidson, Janice S; Martin, Kirsty G; Hayes, Peter C; Simpson, Kenneth J

    2011-01-01

    AIMS Paracetamol (acetaminophen) hepatotoxicity is the commonest cause of acute liver failure (ALF) in the UK. Conflicting data regarding the outcomes of paracetamol-induced ALF resulting from different overdose patterns are reported. METHODS Using prospectively defined criteria, we have analysed the impact of overdose pattern upon outcome in a cohort of 938 acute severe liver injury patients admitted to the Scottish Liver Transplantation Unit. RESULTS Between 1992 and 2008, 663 patients were admitted with paracetamol-induced acute severe liver injury. Of these patients, 500 (75.4%) had taken an intentional paracetamol overdose, whilst 110 (16.6%) had taken an unintentional overdose. No clear overdose pattern could be determined in 53 (8.0%). Unintentional overdose patients were significantly older, more likely to abuse alcohol, and more commonly overdosed on compound narcotic/paracetamol analgesics compared with intentional overdose patients. Unintentional overdoses had significantly lower admission paracetamol and alanine aminotransferase concentrations compared with intentional overdoses. However, unintentional overdoses had greater organ dysfunction at admission, and subsequently higher mortality (unintentional 42/110 (38.2%), intentional 128/500 (25.6%), P paracetamol overdose is associated with increased mortality compared with intentional paracetamol overdose, despite lower admission paracetamol concentrations. Alternative prognostic criteria may be required for unintentional paracetamol overdoses. PMID:21219409

  16. Deletion of circadian gene Per1 alleviates acute ethanol-induced hepatotoxicity in mice

    International Nuclear Information System (INIS)

    Wang, Tao; Yang, Ping; Zhan, Yibei; Xia, Lin; Hua, Zichun; Zhang, Jianfa

    2013-01-01

    The severity of ethanol-induced liver injury is associated with oxidative stress and lipid accumulation in the liver. Core circadian clock is known to mediate antioxidative enzyme activity and lipid metabolism. However, the link between circadian clock and ethanol-induced hepatotoxicity remains unclear. Here we showed that extents of acute ethanol-induced liver injury and steatosis in mice exhibit circadian variations consistent with hepatic expression of Period (Per) genes. Mice lacking clock gene Per1 displayed less susceptible to ethanol-induced liver injury, as evidenced by lower serum transaminase activity and less severe histopathological changes. Ethanol-induced lipid peroxidation was alleviated in Per1−/− mice. However, Per1 deletion had no effect on antioxidants depletion caused by ethanol administration. Ethanol-induced triglycerides (TG) accumulation in the serum and liver was significantly decreased in Per1−/− mice compared with that in wild-type (WT) mice. Analysis of gene expression in the liver revealed peroxisome proliferators activated receptor-gamma (PPARγ) and its target genes related to TG synthesis are remarkably down-regulated in Per1−/− mice. HepG2 cells were treated with ethanol at 150 mM for 3 days. Per1 overexpression augmented lipid accumulation after treatment with ethanol in HepG2 cells, but had no effect on ethanol-induced oxidative stress. Expression of genes related to lipogenesis, including PPARγ and its target genes, was up-regulated in cells overexpressing Per1. In conclusion, these results indicated that circadian rhythms of ethanol-induced hepatotoxicity are controlled by clock gene Per1, and deletion of Per1 protected mice from ethanol-induced liver injury by decreasing hepatic lipid accumulation

  17. Hepatoprotective effect of ethanol extract from Berchemia lineate against CCl4-induced acute hepatotoxicity in mice.

    Science.gov (United States)

    Li, Cong; Yi, Li-Tao; Geng, Di; Han, Yuan-Yuan; Weng, Lian-Jin

    2015-05-01

    The roots of Berchemia lineate (L.) DC. (Rhamnaceae) have been long used as a remedy for the treatment of some diseases in Guangxi Province, China. The present study investigates the hepatoprotective effect of Berchemia lineate ethanol extract (BELE) on CCl4-induced acute liver damage in mice. Effect of BELE administrated for 7 consecutive days was evaluated in mice by the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), albulin (ALB), globulin (GLB), and total protein (TP) levels, as well as liver superoxide dismutase (SOD) activity and malondialdehyde (MDA) level. Moreover, histopathological examinations were also taken. Compared with the model group, administration of 400 mg/kg BELE for 7 d in mice significantly decreased the serum ALT (56.25 U/L), AST (297.67 U/L), ALP (188.20 U/L), and TBIL (17.90 mol/L), along with the elevation of TP (64.67 g/L). In addition, BELE (100, 200, and 400 mg/kg, i.g.) treated mice recorded a dose-dependent increment of SOD (291.17, 310.32, and 325.67 U/mg prot) and reduction of MDA (7.27, 6.77, and 5.33 nmol/mg prot) levels. Histopathological examinations also confirmed that BELE can ameliorate CCl4-induced liver injuries, characterized by extensive hepatocellular degeneration/necrosis, inflammatory cell infiltration, congestion, and sinusoidal dilatation. The results indicated that BELE possessed remarkable protective effect against acute hepatotoxicity and oxidative injuries induced by CCl4, and that the hepatoprotective effects of BELE may be due to both the inhibition of lipid peroxidation and the increase of antioxidant activity.

  18. Gene expression data from acetaminophen-induced toxicity in human hepatic in vitro systems and clinical liver samples

    Directory of Open Access Journals (Sweden)

    Robim M. Rodrigues

    2016-06-01

    Full Text Available This data set is composed of transcriptomics analyses of (i liver samples from patients suffering from acetaminophen-induced acute liver failure (ALF and (ii hepatic cell systems exposed to acetaminophen and their respective controls. The in vitro systems include widely employed cell lines i.e. HepaRG and HepG2 cells as well as a novel stem cell-derived model i.e. human skin-precursors-derived hepatocyte-like cells (hSKP-HPC. Data from primary human hepatocytes was also added to the data set “Open TG-GATEs: a large-scale toxicogenomics database” (Igarashi et al., 2015 [1]. Changes in gene expression due to acetaminophen intoxication as well as comparative information between human in vivo and in vitro samples are provided. The microarray data have been deposited in NCBI׳s Gene Expression Omnibus and are accessible through GEO Series accession number GEO: GSE74000. The provided data is used to evaluate the predictive capacity of each hepatic in vitro system and can be directly compared with large-scale publically available toxicogenomics databases. Further interpretation and discussion of these data feature in the corresponding research article “Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems” (Rodrigues et al., 2016 [2].

  19. Evaluation of Hepatoprotective Activity of Adansonia digitata Extract on Acetaminophen-Induced Hepatotoxicity in Rats

    Directory of Open Access Journals (Sweden)

    Abeer Hanafy

    2016-01-01

    Full Text Available The methanol extract of the fruit pulp of Adansonia digitata L. (Malvaceae was examined for its hepatoprotective activity against liver damage induced by acetaminophen in rats. The principle depends on the fact that administration of acetaminophen will be associated with development of oxidative stress. In addition, hepatospecific serum markers will be disturbed. Treatment of the rats with the methanol extract of the fruit pulp of Adansonia digitata L. prior to administration of acetaminophen significantly reduced the disturbance in liver function. Liver functions were measured by assessment of total protein, total bilirubin, ALP, ALT, and AST. Oxidative stress parameter and antioxidant markers were also evaluated. Moreover, histopathological evaluation was performed in order to assess liver case regarding inflammatory infiltration or necrosis. Animals were observed for any symptoms of toxicity after administration of extract of the fruit pulp of Adansonia digitata L. to ensure safety of the fruit extract.

  20. Therapeutic potential of alpha-ketoglutarate against acetaminophen-induced hepatotoxicity in rats

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    Lalita Mehra

    2016-01-01

    Full Text Available Objective: Alpha-ketoglutarate (α-KG is a cellular intermediary metabolite of Krebs cycle, involved in energy metabolism, amino acid synthesis, and nitrogen transport. It is available over-the-counter and marketed as a nutritional supplement. There is a growing body of evidence to suggest that dietary α-KG has the potential to maintain cellular redox status and thus can protect various oxidative stress induced disease states. The aim of the present study was to investigate the hepatoprotective role of α-KG in acetaminophen (APAP induced toxicity in rats. Materials and Methods: Animals were divided into three groups of six animals each. Group I (Vehicle control: Normal Saline, Group II (APAP: A single intraperitoneal injection of 0.6 g/kg, Group III (APAP + α-KG: APAP as in Group II with α-KG treatment at a dose of 2 g/kg, orally for 5 days. Then the levels of alanine aminotransferase (ALT, aspartate aminotransferase (AST, and alkaline phosphatase (ALP with oxidative stress markers including malondialdehyde (MDA, reduced glutathione (GSH, superoxide dismutase (SOD, catalase (CAT, and histopathology were analyzed. Results: The results indicate that APAP caused significant elevations in ALT, AST, ALP, and MDA levels, while GSH, SOD, and CAT were significantly depleted while co-administration of α-KG showed a significant (P < 0.05 reduction in the severity of these damages. Histologically, the liver showed inflammation and necrosis after APAP treatment, which were significantly restored with co-administration of α-KG. Conclusion: These results indicate the possible therapeutic potential of α-KG in protecting liver damage by APAP in rats.

  1. Influence of sex and developmental stage on acute hepatotoxic and inflammatory responses to liver procarcinogens in the mouse

    International Nuclear Information System (INIS)

    Hanna, Daniel; Riedmaier, Ariane Emami; Sugamori, Kim S.; Grant, Denis M.

    2016-01-01

    The incidence of liver cancer is higher in men than in women. This sex difference is also observed in murine tumor induction models that result in the appearance of liver tumors in adult mice following their exposure on postnatal days 8 and/or 15 to carcinogens such as 4-aminobiphenyl (ABP) or diethylnitrosamine (DEN). Previous studies performed in adult mice showed that acute hepatotoxic and inflammatory responses to high-dose DEN exposure were greater in males than in females, leading to the suggestion that these responses could account for the sex difference in tumor development. We also recently observed that female but not male mice exposed postnatally to ABP had slightly increased expression of the antioxidant defense genes Nqo1 and Ggt1, which are regulated by the oxidative stress response protein nuclear factor erythroid 2-related factor 2 (NRF2), while expression of Hmox1 was increased in both sexes. The goal of the present study was therefore to compare selected acute hepatotoxic, inflammatory and oxidative stress defense responses to ABP, DEN, or the prototype hepatotoxicant carbon tetrachloride (CCl 4 ), in male and female mice exposed to these chemicals either postnatally or as adults. Exposure of adult mice to ABP, DEN or CCl 4 produced a 2-fold greater acute elevation in serum levels of the hepatotoxicity biomarker alanine aminotransferase (ALT) in males than in females, while levels of the inflammatory biomarker interleukin-6 (IL-6) showed no sex difference. However, treatment of immature mice with either ABP or DEN using standard tumor-inducing postnatal exposure protocols produced no increase in serum ALT or IL-6 levels in either males or females, while CCl 4 produced a 40-fold ALT elevation but with no sex difference. Basal expression of the NRF2-responsive gene Nqo1 was higher in adult females than in males, but there was no sex difference in basal expression of Ggt1 or Hmox1. Sexually immature animals showed no sex difference in basal

  2. Hepatoprotective Effect of Metadoxine on Acetaminophen-induced Liver Toxicity in Mice

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    Parvin Mazraati

    2018-01-01

    Full Text Available Background: Metadoxine (pyridoxine pyrrolidone carboxylate is considered to be a beneficial agent for the treatment of experimental hepatotoxicity due to alcohol, CCl4, and bile duct ligation. Hence, the therapeutic effect of metadoxine and N-acetylcysteine (NAC as reference drug was investigated in mice exposed to acute hepatotoxicity induced by a single oral toxic dose of acetaminophen (650 mg/kg. Materials and Methods: Metadoxine (200 and 400 mg/kg and NAC (300 mg/kg were given orally (p. o., 2 h after acetaminophen administration. Serum aminotransferases, aspartate transaminase (AST, alanine transaminase (ALT, alkaline phosphatase (ALP, total bilirubin, hepatic glutathione (GSH, and malondialdehyde (MDA levels were determined for evaluating the extent of hepatotoxicity due to acetaminophen and its protection by metadoxine. Results: Findings indicated that metadoxine significantly reduced the level of serum ALT, AST, and ALP but not total bilirubin which increased by acetaminophen intoxication. Administration of metadoxine also attenuated oxidative stress by suppressing lipid peroxidation (MDA and prevented the depletion of reduced GSH level which caused by acetaminophen toxicity. Besides, metadoxine ameliorated histopathological hepatic tissue injury induced by acetaminophen. Conclusion: In most parameters examined, the effect of metadoxine was comparable to NAC. Hence, metadoxine could be considered as a beneficial therapeutic candidate to protect against acute acetaminophen hepatotoxicity.

  3. Alpha-fetoprotein is a predictor of outcome in acetaminophen-induced liver injury

    DEFF Research Database (Denmark)

    Schmidt, Lars E; Dalhoff, Kim

    2005-01-01

    An increase in alpha-fetoprotein (AFP) following hepatic necrosis is considered indicative of hepatic regeneration. This study evaluated the prognostic value of serial AFP measurements in patients with severe acetaminophen-induced liver injury. Prospectively, serial measurements of AFP were...

  4. DYNAMICS OF CLINICAL AND BIOCHEMICAL PARAMETERS AND FUNCTIONAL STATE OF THE AUTONOMIC NERVOUS SYSTEM IN PATIENTS WITH ACUTE HEPATITIS B WITH CHRONIC ALCOHOL USE IN HEPATOTOXIC DOSES

    Directory of Open Access Journals (Sweden)

    O. O. Furyk

    2014-02-01

    Full Text Available Relevance of hepatitis B due to the high incidence complexity of pathogenesis, ineffective treatment, severe consequences of the disease. Among combined lesions of the liver, special attention is paid to viral-alcoholic type. One of the mechanisms of chronic hepatitis of different etiology is violation of the functional activity of the autonomic nervous system. The aim of this work- to determine the dynamics of spectral indices of heart rate variability in patients with acute hepatitis B from chronic use of alcohol in hepatotoxic doses. Materials and methods. 133 patients with acute hepatitis B were under observation. Patients were divided into groups taking account the presence or absence of chronic use of alcohol in hepatotoxic doses and using the classification of alcohol consumption based on the frequency and dose of consumed alcohol. I group comprised 52 patients with chronic use of alcohol in the hepatotoxic doses, II group consisted of 81 patient without this factor. Heart rate variability was diagnosed using computer cardiointervalometry performed by electrocardiographic diagnostic system CardioLab-2000. 20 healthy individuals were in the control group. Results and discussion. Prodromal period in patients of the I group was longer (p0,05. However, only patients in group I had marked hemorrhagic manifestations (5,8 % and itching (7.7%. Average serum total bilirubin level was higher (p<0,05 in patients from the I group than in patients from II group. Functional state of autonomic nervous system in patients of both groups were decreased in acute period (vagotonia. Period of convalescence in patients from the I group was accompanied by more severe autonomic dysfunction in 33,6 % (p<0,05. Conclusions. 1. Acute hepatitis B in patients with chronic alcohol use in hepatotoxic doses is characterized by longer (p<0,05 prodrome, cholestatic (7,7% and hemorrhagic manifestations (5,8%, higher levels of hyperbilirubinemia (p<0,05, and during

  5. NADH:ubiquinone reductase and succinate dehydrogenase activity in the liver of rats with acetaminophen-induced toxic hepatitis on the background of alimentary protein deficiency

    Directory of Open Access Journals (Sweden)

    G. P. Kopylchuk

    2015-02-01

    Full Text Available The ratio between the redox forms of the nicotinamide coenzymes and key enzymatic activity of the I and II respiratory chain complexes in the liver cells mitochondria of rats with acetaminophen-induced hepatitis under the conditions of alimentary deprivation of protein was studied. It was estimated, that under the conditions of acute acetaminophen-induced hepatitis of rats kept on a low-protein diet during 4 weeks a significant decrease of the NADH:ubiquinone reductase and succinate dehydrogenase activity with simultaneous increase of the ratio between redox forms of the nicotinamide coenzymes (NAD+/NADН is observed compared to the same indices in the liver cells of animals with experimental hepatitis kept on the ration balanced by all nutrients. Results of research may become basic ones for the biochemical rationale for the approaches directed to the correction and elimination of the consequences­ of energy exchange in the toxic hepatitis, induced on the background of protein deficiency.

  6. Protective Effects of Cultivated Ginseng, Cultivated Wild Ginseng of Korean and Chinese Against CCl4 and t-BHP Induced Acute Hepatotoxicity in ICR Mice

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    Kim, Young-Jin

    2007-02-01

    Full Text Available Objectives : This study was aimed at investigating live protection mechanism of Cultivated Ginseng and Cultivated Wild Ginseng of Korean and Chinese by inducing liver toxicity through and t-BHP in mice and evaluated serological findings. Methods : Experiment groups was categorized into untreated normal group, treated control group, and orally administered Cultivated Ginseng and Cultivated Wild Ginseng of Korean and Chinese experimental groups. At the termination of experiment, gross examination of the liver as well as Total bilirubin, AST, and ALT contents in the serum were evaluated. Results : 1. In the induced acute hepatotoxicity test, total bilirubin, AST and ALT didn't show significant differences between the control and experimental groups. 2. In the t-BHP induced acute hepatotoxicity test, total bilirubin, AST and ALT didn't show significant differences between the control and experimental groups. Conclusion : Taken together, Cultivated Ginseng and Cultivated Wild Ginseng of Korean and Chinese cannot be effectively used for recovering the liver functions in acute hepatotoxicity tests using and t-BHP. Further researches, for example treated long period, must be tried to verify the efficacies.

  7. Study of acute hepatotoxicity of Equisetum arvense L. in rats Estudo da hepatotoxicidade aguda da Equisetum arvense L. em ratos

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    Nilo César do Vale Baracho

    2009-12-01

    Full Text Available PURPOSE: To evaluate the acute hepatotoxicity of Equisentum arvense L. in rats. METHODS: Fifty Wistar rats were used, these being divided in four groups, one being the control (receiving only water and the other groups receiving graded doses of Equisentum arvense L. (30, 50, and 100mg/kg respectively for 14 days. Blood samples were obtained to determine TGO, TGP, FA, DHL and GT-gamma activities. After that, hepatic tissue samples were collected for the anatomopathologic analysis. RESULTS: The anatomopathologic exam of the hepatic tissue showed organ with preserved lobular structure. In the same way, there was no significant change in the seric activities of the hepatic enzymes when compared to control group. CONCLUSION: The oral treatment with graded doses of Equisentum arvense L. was not able to produce hepatic changes. Further studies are necessary to evaluate the chronic hepatotoxicity of Equisentum arvense L. in rats.OBJETIVO: Investigar a hepatotoxicidade aguda da Equisetum arvense L. em ratos. MÉTODOS: foram utilizados 50 ratos Wistar, os quais foram divididos em quatro grupos, sendo um controle (recebendo apenas água e os outros grupos recebendo doses crescentes de cavalinha (30, 50 e 100mg/Kg, respectivamente por 14 dias. Foram coletadas amostras de sangue para determinação da atividade sérica de TGO, TGP, FA, DHL e gama-GT. Em seguida, foram obtidas amostras de tecido hepático para análise anatomopatológica. RESULTADOS: O exame anatomopatológico de tecido hepático demonstrou órgão com estrutura lobular preservada. Da mesma forma, não houve alteração significativa na atividade sérica das enzimas hepáticas, quando comparado ao grupo controle. CONCLUSÃO: O tratamento com doses crescentes de Equisetum arvense L., não induziu hepatotoxicidade aguda em ratos. Novos estudos são necessários para avaliar a hepatoxicidade crônica de Equisetum arvense L. em ratos.

  8. Hepatoprotective Effect of Citral on Acetaminophen-Induced Liver Toxicity in Mice

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    Nancy Sayuri Uchida

    2017-01-01

    Full Text Available High doses of acetaminophen (APAP lead to acute liver damage. In this study, we evaluated the effects of citral in a murine model of hepatotoxicity induced by APAP. The liver function markers alanine aminotransferase (ALT, aspartate aminotransferase (AST, alkaline phosphatase (ALP, and gamma-glutamyl transferase (γGT were determined to evaluate the hepatoprotective effects of citral. The livers were used to determine myeloperoxidase (MPO activity and nitric oxide (NO production and in histological analysis. The effect of citral on leukocyte migration and antioxidant activity was evaluated in vitro. Citral pretreatment decreased significantly the levels of ALT, AST, ALP, and γGT, MPO activity, and NO production. The histopathological analysis showed an improvement of hepatic lesions in mice after citral pretreatment. Citral inhibited neutrophil migration and exhibited antioxidant activity. Our results suggest that citral protects the liver against liver toxicity induced by APAP.

  9. N-Methyl-3,4-methylenedioxyamphetamine-induced hepatotoxicity in rats: Oxidative stress after acute and chronic administration

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    Ninković Milica

    2004-01-01

    Full Text Available Background. The underlying mechanisms of N-Methyl-3,4-methylenedioxyamphetamine-MDMA-induced hepatotoxicity are still unknown. The aim of this study was to evaluate hepatic oxido-reductive status in the rats liver after the single and repeated administration of MDMA. Methods. MDMA was dissolved in distilled water and administered in the doses of 5 mg, 10 mg, 20 mg, and 40 mg/kg. The animals from the acute experiment were treated per os with the single dose of the appropriate solution, through the orogastric tube. The animals from the chronic experiment were treated per os, with the doses of 5, 10, or 20 mg/kg of MDMA every day during 14 days. The control groups were treated with water only. Eight hours after the last dose, the animals were sacrificed, dissected their livers were rapidly removed, frozen and stored at -70°C until the moment of analysis. The parameters of oxidative stress in the crude mitochondrial fractions of the livers were analyzed. Results. Superoxide dismutase (SOD activity increased in the livers of the animals that were treated with single doses of MDMA. Chronically treated animals showed the increased SOD activity only after the highest dose (20 mg/kg. The content of reduced glutathione decreased in both groups, but the depletion was much more expressed after the single administration. Lipid peroxidation index increased in dose-dependent manner in both groups, being much higher after the single administration. Conclusion. The increased index of lipid peroxidation and the decreased reduced glutathione levels suggested that MDMA application induced the state of oxidative stress in the liver. These changes were much more expressed after the single administration of MDMA.

  10. Parallelogram approach using rat-human In vitro and rat in vivo toxicogenomics predicts acetaminophen-induced hepatotoxicity in humans

    NARCIS (Netherlands)

    Kienhuis, A.S.; Poll, M.C.G. van de; Wortelboer, H.; Herwijnen, M. van; Gottschalk, R.; Jong, C.H.C. de; Boorsma, A.; Paules, R.S.; Kleinjans, J.C.S.; Stierum, R.H.; Delft, J.H.M. van

    2009-01-01

    The frequent use of rodent hepatic in vitro systems in pharmacological and toxicological investigations challenges extrapolation of in vitro results to the situation in vivo and interspecies extrapolation from rodents to humans. The toxicogenomics approach may aid in evaluating relevance of these

  11. Dietary saturated and monounsaturated fats protect against acute acetaminophen hepatotoxicity by altering fatty acid composition of liver microsomal membrane in rats

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    Shim Eugene

    2011-10-01

    Full Text Available Abstract Background Dietary polyunsaturated fats increase liver injury in response to ethanol feeding. We evaluated the effect of dietary corn oil (CO, olive oil (OO, and beef tallow (BT on fatty acid composition of liver microsomal membrane and acute acetaminophen hepatotoxicity. Methods Male Sprague-Dawley rats were fed 15% (wt/wt CO, OO or BT for 6 weeks. After treatment with acetaminophen (600 mg/kg, samples of plasma and liver were taken for analyses of the fatty acid composition and toxicity. Results Treatment with acetaminophen significantly elevated levels of plasma GOT and GPT as well as hepatic TBARS but reduced hepatic GSH levels in CO compared to OO and BT groups. Acetaminophen significantly induced protein expression of cytochrome P450 2E1 in the CO group. In comparison with the CO diet, lower levels of linoleic acid, higher levels of oleic acids and therefore much lower ratios of linoleic to oleic acid were detected in rats fed OO and BT diets. Conclusions Dietary OO and BT produces similar liver microsomal fatty acid composition and may account for less severe liver injury after acetaminophen treatment compared to animals fed diets with CO rich in linoleic acid. These findings imply that types of dietary fat may be important in the nutritional management of drug-induced hepatotoxicity.

  12. Protective Effect of Cymbopogon citratus Essential Oil in Experimental Model of Acetaminophen-Induced Liver Injury.

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    Uchida, Nancy Sayuri; Silva-Filho, Saulo Euclides; Aguiar, Rafael Pazinatto; Wiirzler, Luiz Alexandre Marques; Cardia, Gabriel Fernando Esteves; Cavalcante, Heitor Augusto Otaviano; Silva-Comar, Francielli Maria de Souza; Becker, Tânia Cristina Alexandrino; Silva, Expedito Leite; Bersani-Amado, Ciomar Aparecida; Cuman, Roberto Kenji Nakamura

    2017-01-01

    To investigate the hepatoprotective effect of Cymbopogon citratus or lemongrass essential oil (LGO), it was used in an animal model of acute liver injury induced by acetaminophen (APAP). Swiss mice were pretreated with LGO (125, 250 and 500[Formula: see text]mg/kg) and SLM (standard drug, 200[Formula: see text]mg/kg) for a duration of seven days, followed by the induction of hepatotoxicity of APAP (single dose, 250[Formula: see text]mg/kg). The liver function markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase were determined to evaluate the hepatoprotective effects of the LGO. The livers were used to determine myeloperoxidase (MPO) activity, nitric oxide (NO) production and histological analysis. The effect of LGO on leukocyte migration was evaluated in vitro. Anti-oxidant activity was performed by assessing the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) in vitro. LGO pretreatment decreased significantly the levels of ALT, AST and ALP compared with APAP group. MPO activity and NO production were decreased. The histopathological analysis showed an improved of hepatic lesions in mice after LGO pretreatment. LGO inhibited neutrophil migration and exhibited anti-oxidant activity. Our results suggest that LGO has protective activity against liver toxicity induced by paracetamol.

  13. Effect of corn silk extract on acetaminophen induced renal damage in mice

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    Mehboob, F.; Tahir, M.

    2015-01-01

    To evaluate the protective role of Corn Silk extract on Acetaminophen induced nephrotoxicity in albino mice. Study Design: Laboratory based randomized controlled trials. Place and Duration of Study: The study was carried out in experimental research laboratory University of Health Sciences and Anatomy department, Lahore. The study duration was one year from February 2012 to February 2013. Material and Methods: Twenty seven male albino mice, 6-8 weeks old weighing 30 + 5 gm, were used; these animals were randomly divided into three groups having nine mice in each group. Group A served as control and was given 16.6ml/kg normal saline intraperitoneally on first day of experiment and was sacrificed on 10th day of the experiment. Group B was treated with acetaminophen 600 mg/kg dissolved in 16.6 ml of normal saline intraperitoneally on 1st day of experiment and was sacrificed after 48 hours. Group C was given acetaminophen at a dose of 600 mg/kg intraperitoneally on first day of experiment and then corn silk extract was given by oral route at a dose of 400 mg/kg for next 8 days. The animals were sacrificed on 10th day of the experiment, the kidneys were removed; 3mm three tissue pieces were fixed in 10% formaline; processed and stained with H and E for histological study. Results: It was observed on microscopic examination that Corn silk extract reduced deleterious effects of acetaminophen on tubules of kidney as evidenced by reduction of tubular vacuolation and necrosis, absence of protein casts, vascular congestion and inflammation. Conclusion: It is concluded from current results that corn silk extract protects acetaminophen induced nephrotoxicity. (author)

  14. Eucalyptus globulus extract protects upon acetaminophen-induced kidney damages in male rat

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    Dhibi, Sabah; Mbarki, Sakhria; Elfeki, Abdelfettah; Hfaiedh, Najla

    2014-01-01

    Plants have historically been used in treating many diseases. Eucalyptus globules, a rich source of bioactive compounds, and have been shown to possess antioxidative properties. The purpose of this study, carried out on male Wistar rats, was to evaluate the beneficial effects of Eucalyptus globulus extract upon acetaminophen-induced damages in kidney. Our study is realized in the Department of Biology, Faculty of Sciences of Sfax (Tunisia). 32 Wistar male rats; were divided into 4 batches: a control group (n=8), a group of rats treated with acetaminophen (goomg/kg) by intraperitoneal injection during 4 days (n=8), a group receiving Eucalyptus globulus extract (130 mg of dry leaves/kg/day) in drinking water during 42 days after 2 hours of acetaminophen administration (during 4 days) (n=8) and group received only Eucalyptus (n=8) during 42 days. After 6 weeks, animals from each group were rapidly sacrificed by decapitation. Blood serum was obtained by centrifugation. Under our experimental conditions, acetaminophen poisoning resulted in an oxidative stress evidenced by statistically significant losses in the activities of catalase (CAT), superoxide-dismutase (SOD), glutathione-peroxidase (GPX) activities and an increase in lipids peroxidation level in renal tissue of acetaminophen-treated group compared with the control group. Acetaminophen also caused kidney damage as evident by statistically significant (p<0.05) increase in levels of creatinine and urea and decreased levels of uric acid and proteins in blood. Histological analysis demonstrated alteration of proximal tubules, atrophy of the glomerule and dilatation of urinary space. Previous administration of plant extract is found to alleviate this acetaminophen-induced damage. PMID:24856382

  15. Hepatoprotective and antioxidant effects of Azolla microphylla based gold nanoparticles against acetaminophen induced toxicity in a fresh water common carp fish (Cyprinus carpio L.

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    Selvaraj Kunjiappan

    2015-04-01

    Conclusion: Azolla microphylla phytochemically synthesized GNaP protects liver against oxidative damage and tissue damaging enzyme activities and could be used as an effective protector against acetaminophen-induced hepatic damage in fresh water common carp fish.

  16. Role of the Nalp3 inflammasome in acetaminophen-induced sterile inflammation and liver injury

    International Nuclear Information System (INIS)

    Williams, C. David; Antoine, Daniel J.; Shaw, Patrick J.; Benson, Craig; Farhood, Anwar; Williams, Dominic P.; Kanneganti, Thirumala-Devi; Park, B. Kevin; Jaeschke, Hartmut

    2011-01-01

    Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US and UK. Recent studies implied that APAP-induced injury is partially mediated by interleukin-1β (IL-1β), which can activate and recruit neutrophils, exacerbating injury. Mature IL-1β is formed by caspase-1, dependent on inflammasome activation. The objective of this invetstigation was to evaluate the role of the Nalp3 inflammasome on release of damage associated molecular patterns (DAMPs), hepatic neutrophil accumulation and liver injury (ALT, necrosis) after APAP overdose. Mice deficient for each component of the Nalp3 inflammasome (caspase-1, ASC and Nalp3) were treated with 300 mg/kg APAP for 24 h; these mice had similar neutrophil recruitment and liver injury as APAP-treated C57Bl/6 wildtype animals. In addition, plasma levels of DAMPs (DNA fragments, keratin-18, hypo- and hyper-acetylated forms of high mobility group box-1 protein) were similarly elevated with no significant difference between wildtype and gene knockout mice. In addition, aspirin treatment, which has been postulated to attenuate cytokine formation and the activation of the Nalp3 inflammasome after APAP, had no effect on release of DAMPs, hepatic neutrophil accumulation or liver injury. Together, these data confirm the release of DAMPs and a sterile inflammatory response after APAP overdose. However, as previously reported minor endogenous formation of IL-1β and the activation of the Nalp3 inflammasome have little impact on APAP hepatotoxicity. It appears that the Nalp3 inflammasome is not a promising therapeutic target to treat APAP overdose.

  17. Virgin coconut oil supplementation attenuates acute chemotherapy hepatotoxicity induced by anticancer drug methotrexate via inhibition of oxidative stress in rats.

    Science.gov (United States)

    Famurewa, Ademola C; Ufebe, Odomero G; Egedigwe, Chima A; Nwankwo, Onyebuchi E; Obaje, Godwin S

    2017-03-01

    The emerging health benefit of virgin coconut oil (VCO) has been associated with its potent natural antioxidants; however, the antioxidant and hepatoprotective effect of VCO against methotrexate-induced liver damage and oxidative stress remains unexplored. The study explored the antioxidant and hepatoprotective effects of VCO against oxidative stress and liver damage induced by anticancer drug methotrexate (MTX) in rats. Liver damage was induced in Wistar rats pretreated with dietary supplementation of VCO (5% and 15%) by intraperitoneal administration of MTX (20mg/kg bw) on day 10 only. After 12days of treatment, assays for serum liver biomarkers (aminotransferases), alkaline phosphatase, albumin and total protein as well as hepatic content of malondialdehyde, reduced glutathione and antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) were carried out. Liver was used to examine histopathological changes. MTX administration induced significant increase in serum liver enzymes along with marked decrease in albumin and total protein compared to control group. Hepatic activities of antioxidant enzymes were significantly decreased, while malondialdehyde increased significantly. Treatment with VCO supplemented diet prior to MTX administration attenuated MTX-induced liver injury and oxidative stress evidenced by significant improvements in serum liver markers, hepatic antioxidant enzymes and malondialdehyde comparable to control group. Histopathological alterations were prevented and correlated well with the biochemical indices. The study suggests antioxidant and hepatoprotective effects of VCO supplementation against hepatotoxicity and oxidative damage via improving antioxidant defense system in rats. Our findings may have beneficial application in the management of hepatotoxicity associated with MTX cancer chemotherapy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  18. Review article: herbal and dietary supplement hepatotoxicity.

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    Bunchorntavakul, C; Reddy, K R

    2013-01-01

    Herbal and dietary supplements are commonly used throughout the World. There is a tendency for underreporting their ingestion by patients and the magnitude of their use is underrecognised by Physicians. Herbal hepatotoxicity is not uncommonly encountered, but the precise incidence and manifestations have not been well characterised. To review the epidemiology, presentation and diagnosis of herbal hepatotoxicity. This review will mainly discuss single ingredients and complex mixtures of herbs marketed under a single label. A Medline search was undertaken to identify relevant literature using search terms including 'herbal', 'herbs', 'dietary supplement', 'liver injury', 'hepatitis' and 'hepatotoxicity'. Furthermore, we scanned the reference lists of the primary and review articles to identify publications not retrieved by electronic searches. The incidence rates of herbal hepatotoxicity are largely unknown. The clinical presentation and severity can be highly variable, ranging from mild hepatitis to acute hepatic failure requiring transplantation. Scoring systems for the causality assessment of drug-induced liver injury may be helpful, but have not been validated for herbal hepatotoxicity. Hepatotoxicity features of commonly used herbal products, such as Ayurvedic and Chinese herbs, black cohosh, chaparral, germander, greater celandine, green tea, Herbalife, Hydroxycut, kava, pennyroyal, pyrrolizidine alkaloids, skullcap, and usnic acid, have been individually reviewed. Furthermore, clinically significant herb-drug interactions are also discussed. A number of herbal medicinal products are associated with a spectrum of hepatotoxicity events. Advances in the understanding of the pathogenesis and the risks involved are needed to improve herbal medicine safety. © 2012 Blackwell Publishing Ltd.

  19. Hepatoprotective effects of Arctium lappa on carbon tetrachloride- and acetaminophen-induced liver damage.

    Science.gov (United States)

    Lin, S C; Chung, T C; Lin, C C; Ueng, T H; Lin, Y H; Lin, S Y; Wang, L Y

    2000-01-01

    The root of Arctium lappa Linne (A. lappa) (Compositae), a perennial herb, has been cultivated for a long time as a popular vegetable. In order to investigate the hepatoprotective effects of A. lappa, male ICR mice were injected with carbon tetrachloride (CCl4, 32 microl/kg, i.p.) or acetaminophen (600 mg/kg, i.p.). A. lappa suppressed the SGOT and SGPT elevations induced by CCl4 or acetaminophen in a dose-dependent manner and alleviated the severity of liver damage based on histopathological observations. In an attempt to elucidate the possible mechanism(s) of this hepatoprotective effect, glutathione (GSH), cytochrome P-450 (P-450) and malondialdehyde (MDA) contents were studied. A. lappa reversed the decrease in GSH and P-450 induced by CCl4 and acetaminophen. It was also found that A. lappa decreased the malondialdehyde (MDA) content in CCl4 or acetaminophen-intoxicated mice. From these results, it was suggested that A. lappa could protect the liver cells from CCl4 or acetaminophen-induced liver damages, perhaps by its antioxidative effect on hepatocytes, hence eliminating the deleterious effects of toxic metabolites from CCl4 or acetaminophen.

  20. Gold nanoparticles ameliorate acetaminophen induced hepato-renal injury in rats.

    Science.gov (United States)

    Reshi, Mohd Salim; Shrivastava, Sadhana; Jaswal, Amita; Sinha, Neelu; Uthra, Chhavi; Shukla, Sangeeta

    2017-04-04

    Valuable effects of gold particles have been reported and used in complementary medicine for decades. The aim of this study was to evaluate the therapeutic efficacy of gold nanoparticles (AuNPs) against acetaminophen (APAP) induced toxicity. Albino rats were administered APAP at a dose of 2g/kg p.o. once only. After 24h of APAP intoxication, animals were treated with three different doses of AuNPs (50μg/kg, 100μg/kg, 150μg/kg) orally or silymarin at a dose of 50mg/kg p.o., once only. Animals of all the groups were sacrificed after 24h of last treatment. APAP administered group showed a significant rise in the AST, ALT, SALP, LDH, cholesterol, bilirubin, albumin, urea and creatinine in serum which indicated the hepato-renal damage. A significantly enhanced LPO and a depleted level of GSH were observed in APAP intoxicated rats. Declined activities of SOD and Catalase, after acetaminophen exposure indicated oxidative stress in liver and kidney. The activities of ATPase and glucose-6-Phosphatase were significantly inhibited after APAP administration. AuNPs treatment reversed all variables significantly towards normal level and was found nontoxic. Thus it is concluded that gold nanoparticles played a beneficial role in reducing acetaminophen induced toxicity and can be used in the development of drug against hepatic as well as renal diseases, after further preclinical and clinical studies. Copyright © 2017 Elsevier GmbH. All rights reserved.

  1. Exacerbation of acetaminophen hepatotoxicity by the anthelmentic drug fenbendazole.

    Science.gov (United States)

    Gardner, Carol R; Mishin, Vladimir; Laskin, Jeffrey D; Laskin, Debra L

    2012-02-01

    Fenbendazole is a broad-spectrum anthelmintic drug widely used to prevent or treat nematode infections in laboratory rodent colonies. Potential interactions between fenbendazole and hepatotoxicants such as acetaminophen are unknown, and this was investigated in this study. Mice were fed a control diet or a diet containing fenbendazole (8-12 mg/kg/day) for 7 days prior to treatment with acetaminophen (300 mg/kg) or phosphate buffered saline. In mice fed a control diet, acetaminophen administration resulted in centrilobular hepatic necrosis and increases in serum transaminases, which were evident within 12 h. Acetaminophen-induced hepatotoxicity was markedly increased in mice fed the fenbendazole-containing diet, as measured histologically and by significant increases in serum transaminase levels. Moreover, in mice fed the fenbendazole-containing diet, but not the control diet, 63% mortality was observed within 24 h of acetaminophen administration. Fenbendazole by itself had no effect on liver histology or serum transaminases. To determine if exaggerated hepatotoxicity was due to alterations in acetaminophen metabolism, we analyzed sera for the presence of free acetaminophen and acetaminophen-glucuronide. We found that there were no differences in acetaminophen turnover. We also measured cytochrome P450 (cyp) 2e1, cyp3a, and cyp1a2 activity. Whereas fenbendazole had no effect on the activity of cyp2e1 or cyp3a, cyp1a2 was suppressed. A prolonged suppression of hepatic glutathione (GSH) was also observed in acetaminophen-treated mice fed the fenbendazole-containing diet when compared with the control diet. These data demonstrate that fenbendazole exacerbates the hepatotoxicity of acetaminophen, an effect that is related to persistent GSH depletion. These findings are novel and suggest a potential drug-drug interaction that should be considered in experimental protocols evaluating mechanisms of hepatotoxicity in rodent colonies treated with fenbendazole.

  2. Evaluation of hepatoprotective effect of methanolic extract of Clitoria ternatea (Linn. flower against acetaminophen-induced liver damage

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    Kuppan Nithianantham

    2013-08-01

    Full Text Available Objective: To evaluate the hepatoprotective and antioxidant activity of Clitoria ternatea (C. ternatea flower extract against acetaminophen-induced liver toxicity. Methods: The antioxidant property of C. ternatea flower extract was investigated by employing established in vitro antioxidant assay. The C. ternatea flower extract was studied in this work for its hepatoprotective effect against acetaminophen-induced liver toxicity in mice. Activity was measured by monitoring the levels of aspartate aminotransferase, alanine aminotransferase, billirubin and glutathione with histopathological analysis. Results: The amount of total phenolics and flavonoids were estimated to be 105.40依2.47 mg/g gallic acid equivalent and 72.21依0.05 mg/g catechin equivalent respectively. The antioxidant activity of C. ternatea flower extract was 68.9% at a concentration of 1 mg/mL and was also concentration dependant, with an IC 50 value of 327.00 µg/mL. The results of acetaminophen-induced liver toxicity experiment showed that mice treated with the extract (200 mg/kg showed a significant decrease in alanine aminotransferase, aspartate aminotransferase, and bilirubin levels, which were all elevated in the paracetamol group (P<0.05. Meanwhile, the level of glutathione was found to be restored in extract treated animals compared to the groups treated with acetaminophen alone (P<0.05. Therapy of extract also showed its protective effect on histopathological alterations and supported the biochemical finding. Conclusion: The present work confirmed the hepatoprotective effect of C. ternatea flower against model hepatotoxicant acetaminophen.

  3. Risk prediction of hepatotoxicity in paracetamol poisoning.

    Science.gov (United States)

    Wong, Anselm; Graudins, Andis

    2017-09-01

    Paracetamol (acetaminophen) poisoning is the most common cause of acute liver failure in the developed world. A paracetamol treatment nomogram has been used for over four decades to help determine whether patients will develop hepatotoxicity without acetylcysteine treatment, and thus indicates those needing treatment. Despite this, a small proportion of patients still develop hepatotoxicity. More accurate risk predictors would be useful to increase the early detection of patients with the potential to develop hepatotoxicity despite acetylcysteine treatment. Similarly, there would be benefit in early identification of those with a low likelihood of developing hepatotoxicity, as this group may be safely treated with an abbreviated acetylcysteine regimen. To review the current literature related to risk prediction tools that can be used to identify patients at increased risk of hepatotoxicity. A systematic literature review was conducted using the search terms: "paracetamol" OR "acetaminophen" AND "overdose" OR "toxicity" OR "risk prediction rules" OR "hepatotoxicity" OR "psi parameter" OR "multiplication product" OR "half-life" OR "prothrombin time" OR "AST/ALT (aspartate transaminase/alanine transaminase)" OR "dose" OR "biomarkers" OR "nomogram". The search was limited to human studies without language restrictions, of Medline (1946 to May 2016), PubMed and EMBASE. Original articles pertaining to the theme were identified from January 1974 to May 2016. Of the 13,975 articles identified, 60 were relevant to the review. Paracetamol treatment nomograms: Paracetamol treatment nomograms have been used for decades to help decide the need for acetylcysteine, but rarely used to determine the risk of hepatotoxicity with treatment. Reported paracetamol dose and concentration: A dose ingestion >12 g or serum paracetamol concentration above the treatment thresholds on the paracetamol nomogram are associated with a greater risk of hepatotoxicity. Paracetamol elimination half

  4. Hydrazine inhalation hepatotoxicity.

    Science.gov (United States)

    Kao, Yung Hsiang; Chong, C H; Ng, W T; Lim, D

    2007-10-01

    Abstract Hydrazine is a hazardous chemical commonly used as a reactant in rocket and jet fuel cells. Animal studies have demonstrated hepatic changes after hydrazine inhalation. Human case reports of hydrazine inhalation hepatotoxicity are rare. We report a case of mild hepatotoxicity following brief hydrazine vapour inhalation in a healthy young man, which resolved completely on expectant management.

  5. Mitochondrial–Lysosomal Axis in Acetaminophen Hepatotoxicity

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    Anna Moles

    2018-05-01

    Full Text Available Acetaminophen (APAP toxicity is the most common cause of acute liver failure and a major indication for liver transplantion in the United States and Europe. Although significant progress has been made in understanding the molecular mechanisms underlying APAP hepatotoxicity, there is still an urgent need to find novel and effective therapies against APAP-induced acute liver failure. Hepatic APAP metabolism results in the production of the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI, which under physiological conditions is cleared by its conjugation with glutathione (GSH to prevent its targeting to mitochondria. APAP overdose or GSH limitation leads to mitochondrial NAPQI-protein adducts formation, resulting in oxidative stress, mitochondrial dysfunction, and necrotic cell death. As mitochondria are a major target of APAP hepatotoxicity, mitochondrial quality control and clearance of dysfunctional mitochondria through mitophagy, emerges as an important strategy to limit oxidative stress and the engagement of molecular events leading to cell death. Recent evidence has indicated a lysosomal–mitochondrial cross-talk that regulates APAP hepatotoxicity. Moreover, as lysosomal function is essential for mitophagy, impairment in the fusion of lysosomes with autophagosomes-containing mitochondria may compromise the clearance of dysfunctional mitochondria, resulting in exacerbated APAP hepatotoxicity. This review centers on the role of mitochondria in APAP hepatotoxicity and how the mitochondrial/lysosomal axis can influence APAP-induced liver failure.

  6. Evaluation of the Hepatoprotective Effects of Lantadene A, a Pentacyclic Triterpenoid of Lantana Plants against Acetaminophen-induced Liver Damage

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    Sreenivasan Sasidharan

    2012-11-01

    Full Text Available The aim of the present study was to evaluate the hepatoprotective activity of lantadene A against acetaminophen-induced liver toxicity in mice was studied. Activity was measured by monitoring the levels of aspartate aminotransferase (AST, alanine aminotransferase (ALT, alkaline phosphatase (ALP and bilirubin, along with histo-pathological analysis. Silymarin was used as positive control. A bimodal pattern of behavioural toxicity was exhibited by the lantadene A-treated group at the beginning of the treatment. However, treatment with lantadene A and silymarin resulted in an increase in the liver weight compared with the acetaminophen treated group. The results of the acetaminophen-induced liver toxicity experiments showed that mice treated with lantadene A (500 mg/kg showed a significant decrease in the activity of ALT, AST and ALP and the level of bilirubin, which were all elevated in the acetaminophen treated group (p < 0.05. Histological studies supported the biochemical findings and a maximum improvement in the histoarchitecture was seen. The lantadene A-treated group showed remarkable protective effects against histopathological alterations, with comparable results to the silymarin treated group. The current study confirmed the hepatoprotective effects of lantadene A against the model hepatotoxicant acetaminophen, which is likely related to its potent antioxidative activity.

  7. Fulltext PDF

    Indian Academy of Sciences (India)

    2016-09-28

    Sep 28, 2016 ... acute toxicity of Triphala Mashi, an Ayurvedic formulation. J. Herb. Pharmacother. ... status in the liver and kidney of young and aged rats. Cell. Biochem. Funct. ... acetaminophen-induced hepatotoxicity in mice. J. Pharmacol.

  8. Aloe vera attenuated liver injury in mice with acetaminophen-induced hepatitis.

    Science.gov (United States)

    Werawatganon, Duangporn; Linlawan, Sittikorn; Thanapirom, Kessarin; Somanawat, Kanjana; Klaikeaw, Naruemon; Rerknimitr, Rungsun; Siriviriyakul, Prasong

    2014-07-08

    An overdose of the acetaminophen causes liver injury. This study aims to examine the anti-oxidative, anti-inflammatory effects of Aloe vera in mice with acetaminophen induced hepatitis. Male mice were randomly divided into three groups (n = 8 each). Control group were given orally distilled water (DW). APAP group were given orally N-acetyl-P-aminophenol (APAP) 400 mg/kg suspended in DW. Aloe vera-treated group were given orally APAP and Aloe vera (150 mg/kg) suspended in DW. Twenty-four hours later, the liver was removed to determine hepatic malondialdehyde (MDA), hepatic glutathione (GSH), the number of interleukin (IL)-12 and IL-18 positive stained cells (%) by immunohistochemistry method, and histopathological examination. Then, the serum was collected to determine transaminase (ALT). In APAP group, ALT, hepatic MDA and the number of IL-12 and IL-18 positive stained cells were significantly increased when compared to control group (1210.50 ± 533.86 vs 85.28 ± 28.27 U/L, 3.60 ± 1.50 vs 1.38 ± 0.15 nmol/mg protein, 12.18 ± 1.10 vs 1.84 ± 1.29%, and 13.26 ± 0.90 vs 2.54 ± 1.29%, P = 0.000, respectively), whereas hepatic GSH was significantly decreased when compared to control group (5.98 ± 0.30 vs 11.65 ± 0.43 nmol/mg protein, P = 0.000). The mean level of ALT, hepatic MDA, the number of IL-12 and IL-18 positive stained cells, and hepatic GSH in Aloe vera-treated group were improved as compared with APAP group (606.38 ± 495.45 vs 1210.50 ± 533.86 U/L, P = 0.024; 1.49 ± 0.64 vs 3.60 ± 1.50 nmol/mg protein, P = 0.001; 5.56 ± 1.25 vs 12.18 ± 1.10%, P = 0.000; 6.23 ± 0.94 vs 13.26 ± 0.90%, P = 0.000; and 10.02 ± 0.20 vs 5.98 ± 0.30 nmol/mg protein, P = 0.000, respectively). Moreover, in the APAP group, the liver showed extensive hemorrhagic hepatic necrosis at all zones while in Aloe vera-treated group, the liver architecture was improved histopathology. APAP overdose can cause liver injury. Our result indicate that Aloe vera attenuate APAP

  9. Acetaminophen-induced Liver Injury is Attenuated in Transgenic fat-1 Mice Endogenously Synthesizing Long-chain n-3 Fatty Acids.

    Science.gov (United States)

    Feng, Ruibing; Wang, Yang; Liu, Conghui; Yan, Chunyan; Zhang, Hang; Su, Huanxing; Kang, Jing X; Shang, Chang-Zhen; Wan, Jian-Bo

    2018-04-18

    Acetaminophen (APAP) overdose-caused hepatotoxicity is the most commonly cause of drugs-induced liver failurecharacterized by oxidative stress, mitochondrial dysfunction, and cell damage. Therapeutic efficacy of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in several models of liver disease is well documented. However, the impacts of n-3 PUFA on APAP hepatotoxicity are not adequately addressed. In this study, the fat-1 transgenic mice that synthesize endogenous n-3 PUFA and wild type (WT) littermates were injected intraperitoneally with APAP at the dose of 400 mg/kg to induce liver injury, and euthanized at 0 h, 2 h, 4 h and 6 h post APAP injection for sampling. APAP overdose caused severe liver injury in WT mice as indicated by serum parameters, histopathological changes and hepatocyte apoptosis, which were remarkably ameliorated in fat-1 mice. These protective effects of n-3 PUFA were associated with regulation of the prolonged JNK activation via inhibition of apoptosis signal-regulating kinase 1 (ASK1) / mitogen-activated protein kinase kinase 4 (MKK4) pathway. Additionally, the augment of endogenous n-3 PUFA reduced nuclear factor kappa B (NF-κB) - mediated inflammation response induced by APAP treatment in the liver. These findings indicate that n-3 PUFA has potent protective effects against APAP-induced acute liver injury, suggesting that n-3 dietary supplement with n-3 PUFA may be a potential therapeutic strategy for the treatment of hepatotoxicity induced by APAP overdose. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Time-course of cadmium-induced acute hepatotoxicity in the rat liver: the role of apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Tzirogiannis, Konstantinos N.; Panoutsopoulos, Georgios I.; Hereti, Rosa I.; Alexandropoulou, Katerina N.; Basayannis, Aristidis C.; Mykoniatis, Michael G. [Department of Experimental Pharmacology, Medical School, Athens University, 75 Mikras Asias St., 115 27, Athens (Greece); Demonakou, Maria D. [Histopathology Laboratory, Sismanoglion G.D. Hospital, Sismanogliou 1, Marousi, Attiki 151 27 (Greece)

    2003-12-01

    Exposure to toxic metals and pollutants is a major environmental problem. Cadmium is a metal causing acute hepatic injury but the mechanism of this phenomenon is poorly understood. In the present study, we investigated the mechanism and time-course of cadmium-induced liver injury in rats, with emphasis being placed on apoptosis in parenchymal and nonparenchymal liver cells. Cadmium (3.5 mg/kg body weight) was injected intraperitoneally and the rats were killed 0, 9, 12, 16, 24, 48 and 60 h later. The extent of liver injury was evaluated for necrosis, apoptosis, peliosis, mitoses and inflammatory infiltration in hematoxylin-eosin-stained liver sections, and by assaying serum enzyme activities. The number of cells that died via apoptosis was quantified by TUNEL assay. The identification of nonparenchymal liver cells and activated Kupffer cells was performed histochemically. Liver regeneration was evaluated by assaying the activity of liver thymidine kinase and by the rate of {sup 3}H-thymidine incorporation into DNA. Both cadmium-induced necrotic cell death and parenchymal cell apoptosis showed a biphasic elevation at 12 and 48 h and peaked at 48 and 12 h, respectively. Nonparenchymal cell apoptosis peaked at 48 h. Peliosis hepatis, another characteristic form of liver injury, was first observed at 16 h and, at all time points, closely correlated with the apoptotic index of nonparenchymal liver cells, where the lesion was also maximial at 48 h. Kupffer cell activation and neutrophil infiltration were minimal for all time points examined. Based on thymidine kinase activity, liver regeneration was found to discern a classic biphasic peak pattern at 12 and 48 h. It was very interesting to observe that cadmium-induced liver injury did not involve inflammation at any time point. Apoptosis seems to be a major mechanism for the removal of damaged cells, and constitutes the major type of cell death in nonparenchymal liver cells. Apoptosis of nonparenchymal cells is the basis

  11. Acetaminophen-Induced Liver Injury Alters the Acyl Ethanolamine-Based Anti-Inflammatory Signaling System in Liver

    Directory of Open Access Journals (Sweden)

    Patricia Rivera

    2017-10-01

    Full Text Available Protective mechanisms against drug-induced liver injury are actively being searched to identify new therapeutic targets. Among them, the anti-inflammatory N-acyl ethanolamide (NAE-peroxisome proliferators activated receptor alpha (PPARα system has gained much interest after the identification of its protective role in steatohepatitis and liver fibrosis. An overdose of paracetamol (APAP, a commonly used analgesic/antipyretic drug, causes hepatotoxicity, and it is being used as a liver model. In the present study, we have analyzed the impact of APAP on the liver NAE-PPARα system. A dose-response (0.5–5–10–20 mM and time-course (2–6–24 h study in human HepG2 cells showed a biphasic response, with a decreased PPARα expression after 6-h APAP incubation followed by a generalized increase of NAE-PPARα system-related components (PPARα, NAPE-PLD, and FAAH, including the NAEs oleoyl ethanolamide (OEA and docosahexaenoyl ethanolamide, after a 24-h exposure to APAP. These results were partially confirmed in a time-course study of mice exposed to an acute dose of APAP (750 mg/kg. The gene expression levels of Pparα and Faah were decreased after 6 h of treatment and, after 24 h, the gene expression levels of Nape-pld and Faah, as well as the liver levels of OEA and palmitoyl ethanolamide, were increased. Repeated APAP administration (750 mg/kg/day up to 4 days also decreased the expression levels of PPARα and FAAH, and increased the liver levels of NAEs. A resting period of 15 days completely restored these impairments. Liver immunohistochemistry in a well-characterized human case of APAP hepatotoxicity confirmed PPARα and FAAH decrements. Histopathological and hepatic damage (Cyp2e1, Caspase3, αSma, Tnfα, and Mcp1-related alterations observed after repeated APAP administration were aggravated in the liver of Pparα-deficient mice. Our results demonstrate that the anti-inflammatory NAE-PPARα signaling system is implicated in liver

  12. Nonacetaminophen Drug-Induced Acute Liver Failure.

    Science.gov (United States)

    Thomas, Arul M; Lewis, James H

    2018-05-01

    Acute liver failure of all causes is diagnosed in between 2000 and 2500 patients annually in the United States. Drug-induced acute liver failure is the leading cause of acute liver failure, accounting for more than 50% of cases. Nonacetaminophen drug injury represents 11% of all cases in the latest registry from the US Acute Liver Failure Study Group. Although rare, acute liver failure is clinically dramatic when it occurs, and requires a multidisciplinary approach to management. In contrast with acetaminophen-induced acute liver failure, non-acetaminophen-induced acute liver failure has a more ominous prognosis with a lower liver transplant-free survival. Copyright © 2018 Elsevier Inc. All rights reserved.

  13. The spleen as an extramedullary source of inflammatory cells responding to acetaminophen-induced liver injury

    International Nuclear Information System (INIS)

    Mandal, Mili; Gardner, Carol R.; Sun, Richard; Choi, Hyejeong; Lad, Sonali; Mishin, Vladimir; Laskin, Jeffrey D.; Laskin, Debra L.

    2016-01-01

    Macrophages have been shown to play a role in acetaminophen (APAP)-induced hepatotoxicity, contributing to both pro- and anti-inflammatory processes. In these studies, we analyzed the role of the spleen as an extramedullary source of hepatic macrophages. APAP administration (300 mg/kg, i.p.) to control mice resulted in an increase in CD11b + infiltrating Ly6G + granulocytic and Ly6G − monocytic cells in the spleen and the liver. The majority of the Ly6G + cells were also positive for the monocyte/macrophage activation marker, Ly6C, suggesting a myeloid derived suppressor cell (MDSC) phenotype. By comparison, Ly6G − cells consisted of 3 subpopulations expressing high, intermediate, and low levels of Ly6C. Splenectomy was associated with increases in mature (F4/80 + ) and immature (F4/80 − ) pro-inflammatory Ly6C hi macrophages and mature anti-inflammatory (Ly6C lo ) macrophages in the liver after APAP; increases in MDSCs were also noted in the livers of splenectomized (SPX) mice after APAP. This was associated with increases in APAP-induced expression of chemokine receptors regulating pro-inflammatory (CCR2) and anti-inflammatory (CX3CR1) macrophage trafficking. In contrast, APAP-induced increases in pro-inflammatory galectin-3 + macrophages were blunted in livers of SPX mice relative to control mice, along with hepatic expression of TNF-α, as well as the anti-inflammatory macrophage markers, FIZZ-1 and YM-1. These data demonstrate that multiple subpopulations of pro- and anti-inflammatory cells respond to APAP-induced injury, and that these cells originate from distinct hematopoietic reservoirs. - Highlights: • Multiple inflammatory cell subpopulations accumulate in the spleen and liver following acetaminophen (APAP) intoxication. • Splenectomy alters liver inflammatory cell populations responding to APAP. • Inflammatory cells accumulating in the liver in response to APAP originate from the spleen and the bone marrow. • Hepatotoxicity is reduced in

  14. The spleen as an extramedullary source of inflammatory cells responding to acetaminophen-induced liver injury

    Energy Technology Data Exchange (ETDEWEB)

    Mandal, Mili, E-mail: milimandal@gmail.com [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Gardner, Carol R., E-mail: cgardner@pharmacy.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Sun, Richard, E-mail: fishpower52@gmail.com [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Choi, Hyejeong, E-mail: choi@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Lad, Sonali, E-mail: sonurose92@gmail.com [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Mishin, Vladimir, E-mail: mishinv@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Laskin, Jeffrey D., E-mail: jlaskin@eohsi.rutgers.edu [Department of Environmental and Occupational Health, School of Public Health, Rutgers University, Piscataway, NJ 08854 (United States); Laskin, Debra L., E-mail: laskin@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States)

    2016-08-01

    Macrophages have been shown to play a role in acetaminophen (APAP)-induced hepatotoxicity, contributing to both pro- and anti-inflammatory processes. In these studies, we analyzed the role of the spleen as an extramedullary source of hepatic macrophages. APAP administration (300 mg/kg, i.p.) to control mice resulted in an increase in CD11b{sup +} infiltrating Ly6G{sup +} granulocytic and Ly6G{sup −} monocytic cells in the spleen and the liver. The majority of the Ly6G{sup +} cells were also positive for the monocyte/macrophage activation marker, Ly6C, suggesting a myeloid derived suppressor cell (MDSC) phenotype. By comparison, Ly6G{sup −} cells consisted of 3 subpopulations expressing high, intermediate, and low levels of Ly6C. Splenectomy was associated with increases in mature (F4/80{sup +}) and immature (F4/80{sup −}) pro-inflammatory Ly6C{sup hi} macrophages and mature anti-inflammatory (Ly6C{sup lo}) macrophages in the liver after APAP; increases in MDSCs were also noted in the livers of splenectomized (SPX) mice after APAP. This was associated with increases in APAP-induced expression of chemokine receptors regulating pro-inflammatory (CCR2) and anti-inflammatory (CX3CR1) macrophage trafficking. In contrast, APAP-induced increases in pro-inflammatory galectin-3{sup +} macrophages were blunted in livers of SPX mice relative to control mice, along with hepatic expression of TNF-α, as well as the anti-inflammatory macrophage markers, FIZZ-1 and YM-1. These data demonstrate that multiple subpopulations of pro- and anti-inflammatory cells respond to APAP-induced injury, and that these cells originate from distinct hematopoietic reservoirs. - Highlights: • Multiple inflammatory cell subpopulations accumulate in the spleen and liver following acetaminophen (APAP) intoxication. • Splenectomy alters liver inflammatory cell populations responding to APAP. • Inflammatory cells accumulating in the liver in response to APAP originate from the spleen and the

  15. Acetaminophen induces xenobiotic-metabolizing enzymes in rat: Impact of a uranium chronic exposure.

    Science.gov (United States)

    Rouas, Caroline; Souidi, Maâmar; Grandcolas, Line; Grison, Stephane; Baudelin, Cedric; Gourmelon, Patrick; Pallardy, Marc; Gueguen, Yann

    2009-11-01

    The extensive use of uranium in civilian and military applications increases the risk of human chronic exposure. Uranium is a slightly radioactive heavy metal with a predominantly chemical toxicity, especially in kidney but also in liver. Few studies have previously shown some effects of uranium on xenobiotic-metabolizing enzymes (XME) that might disturb drug pharmacokinetic. The aim of this study was to determine whether a chronic (9 months) non-nephrotoxic low dose exposure to depleted uranium (DU, 1mg/rat/day) could modify the liver XME, using a single non-hepatotoxic acetaminophen (APAP) treatment (50mg/kg). Most of XME analysed were induced by APAP treatment at the gene expression level but at the protein level only CYP3A2 was significantly increased 3h after APAP treatment in DU-exposed rats whereas it remained at a basal level in unexposed rats. In conclusion, these results showed that a chronic non-nephrotoxic DU exposure specially modify CYP3A2 after a single therapeutic APAP treatment. Copyright © 2009 Elsevier B.V. All rights reserved.

  16. Mechanisms of acetaminophen-induced cell death in primary human hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Yuchao; McGill, Mitchell R.; Dorko, Kenneth [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Kumer, Sean C.; Schmitt, Timothy M.; Forster, Jameson [Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States)

    2014-09-15

    Acetaminophen (APAP) overdose is the most prevalent cause of drug-induced liver injury in western countries. Numerous studies have been conducted to investigate the mechanisms of injury after APAP overdose in various animal models; however, the importance of these mechanisms for humans remains unclear. Here we investigated APAP hepatotoxicity using freshly isolated primary human hepatocytes (PHH) from either donor livers or liver resections. PHH were exposed to 5 mM, 10 mM or 20 mM APAP over a period of 48 h and multiple parameters were assessed. APAP dose-dependently induced significant hepatocyte necrosis starting from 24 h, which correlated with the clinical onset of human liver injury after APAP overdose. Interestingly, cellular glutathione was depleted rapidly during the first 3 h. APAP also resulted in early formation of APAP-protein adducts (measured in whole cell lysate and in mitochondria) and mitochondrial dysfunction, indicated by the loss of mitochondrial membrane potential after 12 h. Furthermore, APAP time-dependently triggered c-Jun N-terminal kinase (JNK) activation in the cytosol and translocation of phospho-JNK to the mitochondria. Both co-treatment and post-treatment (3 h) with the JNK inhibitor SP600125 reduced JNK activation and significantly attenuated cell death at 24 h and 48 h after APAP. The clinical antidote N-acetylcysteine offered almost complete protection even if administered 6 h after APAP and a partial protection when given at 15 h. Conclusion: These data highlight important mechanistic events in APAP toxicity in PHH and indicate a critical role of JNK in the progression of injury after APAP in humans. The JNK pathway may represent a therapeutic target in the clinic. - Highlights: • APAP reproducibly causes cell death in freshly isolated primary human hepatocytes. • APAP induces adduct formation, JNK activation and mitochondrial dysfunction in PHH. • Mitochondrial adducts and JNK translocation are delayed in PHH compared to

  17. Reversal of acetaminophen-generated oxidative stress and concomitant hepatotoxicity by a phytopharmaceutical product

    Directory of Open Access Journals (Sweden)

    Afolabi C. Akinmoladun

    2017-03-01

    Full Text Available The increasing popularity of herbal medicine and the well-established health benefits of phytochemicals have spurred the multiplicity of nutraceutical and phytopharmaceutical products. In this study, Trévo™, a nutraceutical and phytopharmaceutical product, was evaluated for beneficial effects in acetaminophen-induced hepatic toxicity in Wistar rats. Animals received Trévo™ (1.5 mL/kg, 3.0 mL/kg or 4.5 mL/kg orally for 14 days. Hepatotoxicity was induced by the oral administration of acetaminophen (2 g/kg, 24 h prior to sacrifice. Biochemical liver function tests, oxidative stress indicators and histoarchitectural changes were evaluated. Acetaminophen administration occasioned significant increase (P < 0.05 in serum bilirubin level and activities of the aminotransferases, alkaline phosphatase, γ-glutamyltransferase and lactate dehydrogenase accompanied by a significant decrease (P < 0.05 in albumin level as well as histopathological alterations in liver sections. Promotion of hepatic oxidative stress by acetaminophen was revealed by significant (P < 0.05 increase in lipid peroxidation, depletion of reduced glutathione, and decrease in superoxide dismutase and catalase activities. Administration of Trévo™ remarkably ameliorated acetaminophen-induced histopathological alterations and changes in serum and tissue biochemical markers. The protective effect of Trévo™ (4.5 mL/kg was at par with that of Silymarin (25 mg/kg. The present study indicates that Trévo™ has notable salubrious effects.

  18. Anti-thromboxane B2 antibodies protect against acetaminophen-induced liver injury in mice

    Directory of Open Access Journals (Sweden)

    Ivan Ćavar

    2011-12-01

    Full Text Available Prostanoids are lipid compounds that mediate a variety of physiological and pathological functions in almost all body tissues and organs. Thromboxane (TX A2 is a powerful inducer of platelet aggregation and vasoconstriction and it has ulcerogenic activity in the gastrointestinal tract. Overdose or chronic use of a high dose of acetaminophen (N-acetyl-paminophenol, APAP is a major cause of acute liver failure in the Western world. We investigated whether TXA2 plays a role in host response to toxic effect of APAP. CBA/H Zg mice of both sexes were intoxicated with a single lethal or high sublethal dose of APAP, which was administered to animals by oral gavage. The toxicity of APAP was determined by observing the survival of mice during 48 h, by measuring concentration of alanine-aminotransferase (ALT in plasma 20-22 h after APAP administration and by liver histology. The results have shown that anti-thromboxane (TX B2 antibodies (anti-TXB2 and a selective inhibitor of thromboxane (TX synthase, benzylimidazole (BZI, were significantly hepatoprotective, while a selective thromboxane receptor (TPR antagonist, daltroban, was slightly protective in this model of acute liver injury. A stabile metabolite of TXA2, TXB2, and a stabile agonist of TPR, U-46619, had no influence on APAP-induced liver damage. Our findings suggest that TXA2 has a pathogenic role in acute liver toxicity induced with APAP, which was highly abrogated by administration of anti-TXB2. According to our results, this protection is mediated, at least in part, through decreased production of TXB2 by liver fragments ex vivo.

  19. Role and mechanisms of autophagy in acetaminophen-induced liver injury.

    Science.gov (United States)

    Chao, Xiaojuan; Wang, Hua; Jaeschke, Hartmut; Ding, Wen-Xing

    2018-04-23

    Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in the USA and many other countries. Although the metabolism and pathogenesis of APAP has been extensively investigated for decades, the mechanisms by which APAP induces liver injury are incompletely known, which hampers the development of effective therapeutic approaches to tackle this important clinical problem. Autophagy is a highly conserved intracellular degradation pathway, which aims at recycling cellular components and damaged organelles in response to adverse environmental conditions and stresses as a survival mechanism. There is accumulating evidence indicating that autophagy is activated in response to APAP overdose in specific liver zone areas, and pharmacological activation of autophagy protects against APAP-induced liver injury. Increasing evidence also suggests that hepatic autophagy is impaired in nonalcoholic fatty livers (NAFLD), and NAFLD patients are more susceptible to APAP-induced liver injury. Here, we summarized the current progress on the role and mechanisms of autophagy in protecting against APAP-induced liver injury. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Patients with the worst outcomes after paracetamol (acetaminophen)-induced liver failure have an early monocytopenia.

    Science.gov (United States)

    Moore, J K; MacKinnon, A C; Man, T Y; Manning, J R; Forbes, S J; Simpson, K J

    2017-02-01

    Acute liver failure (ALF) is associated with significant morbidity and mortality. Studies have implicated the immune response, especially monocyte/macrophages as being important in dictating outcome. To investigate changes in the circulating monocytes and other immune cells serially in patients with ALF, relate these with cytokine concentrations, monocyte gene expression and patient outcome. In a prospective case-control study in the Scottish Liver Transplant Unit, Royal Infirmary Edinburgh, 35 consecutive patients admitted with paracetamol-induced liver failure (POD-ALF), 10 patients with non-paracetamol causes of ALF and 16 controls were recruited. The peripheral blood monocyte phenotype was analysed by flow cytometry, circulating cytokines quantified by protein array and monocyte gene expression array performed and related to outcome. On admission, patients with worst outcomes after POD-ALF had a significant monocytopenia, characterised by reduced classical and expanded intermediate monocyte population. This was associated with reduced circulating lymphocytes and natural killer cells, peripheral cytokine patterns suggestive of a 'cytokine storm' and increased concentrations of cytokines associated with monocyte egress from the bone marrow. Gene expression array did not differentiate patient outcome. At day 4, there was no significant difference in monocyte, lymphocyte or natural killer cells between survivors and the patients with adverse outcomes. Severe paracetamol liver failure is associated with profound changes in the peripheral blood compartment, particularly in monocytes, related with worse outcomes. This is not seen in patients with non-paracetamol-induced liver failure. Significant monocytopenia on admission may allow earlier clarification of prognosis, and it highlights a potential target for therapeutic intervention. © 2016 John Wiley & Sons Ltd.

  1. Hepatotoxicity of amiodarone

    DEFF Research Database (Denmark)

    Rumessen, J J

    1986-01-01

    of the hepatotoxicity of amiodarone is given. It is concluded that solid evidence exists of hepatic injury due to amiodarone treatment, including steatosis, alterations resembling alcoholic hepatitis, cholestatic hepatitis and micronodular cirrhosis of the liver. Patients receiving amiodarone should be regularly......Amiodarone has proved very effective in the treatment of otherwise resistant cardiac tachyarrhythmias. The use of amiodarone has, however, been limited due to its serious side-effects. A patient with cholestatic hepatitis due to amiodarone treatment is presented below and a review...... screened with respect to hepatic enzyme levels. Therapy should be discontinued on the suspicion of cholestatic injury or hepatomegaly....

  2. Acetaminophen-induced liver injury in rats and mice: Comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity

    International Nuclear Information System (INIS)

    McGill, Mitchell R.; Williams, C. David; Xie, Yuchao; Ramachandran, Anup; Jaeschke, Hartmut

    2012-01-01

    Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the West. In mice, APAP hepatotoxicity can be rapidly induced with a single dose. Because it is both clinically relevant and experimentally convenient, APAP intoxication has become a popular model of liver injury. Early data demonstrated that rats are resistant to APAP toxicity. As a result, mice are the preferred species for mechanistic studies. Furthermore, recent work has shown that the mechanisms of APAP toxicity in humans are similar to mice. Nevertheless, some investigators still use rats. New mechanistic information from the last forty years invites a reevaluation of the differences between these species. Comparison may provide interesting insights and confirm or exclude the rat as an option for APAP studies. To this end, we treated rats and mice with APAP and measured parameters of liver injury, APAP metabolism, oxidative stress, and activation of the c-Jun N-terminal kinase (JNK). Consistent with earlier data, we found that rats were highly resistant to APAP toxicity. Although overall APAP metabolism was similar in both species, mitochondrial protein adducts were significantly lower in rats. Accordingly, rats also had less oxidative stress. Finally, while mice showed extensive activation and mitochondrial translocation of JNK, this could not be detected in rat livers. These data support the hypothesis that mitochondrial dysfunction is critical for the development of necrosis after APAP treatment. Because mitochondrial damage also occurs in humans, rats are not a clinically relevant species for studies of APAP hepatotoxicity. Highlights: ► Acetaminophen overdose causes severe liver injury only in mice but not in rats. ► APAP causes hepatic GSH depletion and protein adduct formation in rats and mice. ► Less protein adducts were measured in rat liver mitochondria compared to mouse. ► No oxidant stress, peroxynitrite formation or JNK activation was present in rats. ► The

  3. Translocation of iron from lysosomes to mitochondria during acetaminophen-induced hepatocellular injury: Protection by starch-desferal and minocycline.

    Science.gov (United States)

    Hu, Jiangting; Kholmukhamedov, Andaleb; Lindsey, Christopher C; Beeson, Craig C; Jaeschke, Hartmut; Lemasters, John J

    2016-08-01

    Acetaminophen (APAP) overdose causes hepatotoxicity involving mitochondrial dysfunction and the mitochondrial permeability transition (MPT). Iron is a critical catalyst for ROS formation, and reactive oxygen species (ROS) play an important role in APAP-induced hepatotoxicity. Previous studies show that APAP disrupts lysosomes, which release ferrous iron (Fe(2+)) into the cytosol to trigger the MPT and cell killing. Here, our aim was to investigate whether iron released from lysosomes after APAP is then taken up into mitochondria via the mitochondrial electrogenic Ca(2+), Fe(2+) uniporter (MCFU) to cause mitochondrial dysfunction and cell death. Hepatocytes were isolated from fasted male C57BL/6 mice. Necrotic cell killing was assessed by propidium iodide fluorimetry. Mitochondrial membrane potential (ΔΨ) was visualized by confocal microscopy of rhodamine 123 (Rh123) and tetramethylrhodamine methylester (TMRM). Chelatable Fe(2+) was monitored by quenching of calcein (cytosol) and mitoferrofluor (MFF, mitochondria). ROS generation was monitored by confocal microscopy of MitoSox Red and plate reader fluorimetry of chloromethyldihydrodichlorofluorescein diacetate (cmH2DCF-DA). Administered 1h before APAP (10mM), the lysosomally targeted iron chelator, starch-desferal (1mM), and the MCFU inhibitors, Ru360 (100nM) and minocycline (4µM), decreased cell killing from 83% to 41%, 57% and 53%, respectively, after 10h. Progressive quenching of calcein and MFF began after ~4h, signifying increased cytosolic and mitochondrial chelatable Fe(2+). Mitochondria then depolarized after ~10h. Dipyridyl, a membrane-permeable iron chelator, dequenched calcein and MFF fluorescence after APAP. Starch-desferal, but not Ru360 and minocycline, suppressed cytosolic calcein quenching, whereas starch-desferal, Ru360 and minocycline all suppressed mitochondrial MFF quenching and mitochondrial depolarization. Starch-desferal, Ru360 and minocycline also each decreased ROS formation. Moreover

  4. Acetaminophen (Paracetamol induced acute liver failure – A social problem in an era of increasing tendency to self-treatment

    Directory of Open Access Journals (Sweden)

    Tadeusz Wróblewski

    2015-12-01

    Paracetamol is the cause of many poisonings resulting from the lack of public awareness about toxic interactions with alcohol, and suicide attempts. Acetaminophen-induced acute liver failure concerns a small percentage of patients but can be successfully treated with albumin dialysis, and in extreme cases by liver transplantation.

  5. Serum metabonomics study of the hepatoprotective effect of Corydalis saxicola Bunting on carbon tetrachloride-induced acute hepatotoxicity in rats by (1)H NMR analysis.

    Science.gov (United States)

    Liang, Yong-Hong; Tang, Chao-Ling; Lu, Shi-Yin; Cheng, Bang; Wu, Fang; Chen, Zhao-Ni; Song, Fangming; Ruan, Jun-Xiang; Zhang, Hong-Ye; Song, Hui; Zheng, Hua; Su, Zhi-Heng

    2016-09-10

    Corydalis saxicola Bunting (CS), a traditional Chinese folk medicine, has been effectively used for treating liver disease in Zhuang nationality in South China. However, the exact hepatoprotective mechanism of CS was still looking forward to further elucidation by far. In present work, metabonomic study of biochemical changes in the serum of carbon tetrachloride (CCl4)-induced acute liver injury rats after CS treatment were performed using proton nuclear magnetic resonance ((1)H-NMR) analysis. Metabolic profiling by means of principal components analysis (PCA) and partial least squares-discriminate analysis (PLS-DA) indicated that the metabolic perturbation caused by CCl4 was reduced by CS treatment. A total of 9 metabolites including isoleucine (1), lactate (2), alanine (3), glutamine (4), acetone (5), succinate (6), phosphocholine (7), d-glucose (8) and glycerol (9) were considered as potential biomarkers involved in the development of CCl4-induced acute liver injury. According to pathway analysis by metabolites identified and correlation network construction by Pearson's correlation coefficency matrix, alanine, aspartate and glutamate metabolism and glycerolipid metabolism were recognized as the most influenced metabolic pathways associated with CCl4 injury. As a result, notably, deviations of metabolites 1, 3, 4, 7 and 9 in the process of CCl4-induced acute liver injury were improved by CS treatment, which suggested that CS mediated synergistically abnormalities of the metabolic pathways, composed of alanine, aspartate and glutamate metabolism and glycerolipid metabolism. In this study, it was the first report to investigate the hepatoprotective effect of the CS based on metabonomics strategy, which may be a potentially powerful tool to interpret the action mechanism of traditional Chinese folk medicines. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Transition between acute and chronic hepatotoxicity in mice is associated with impaired energy metabolism and induction of mitochondrial heme oxygenase-1.

    Directory of Open Access Journals (Sweden)

    Aniket Nikam

    Full Text Available The formation of protein inclusions is frequently associated with chronic metabolic diseases. In mice, short-term intoxication with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC leads to hepatocellular damage indicated by elevated serum liver enzyme activities, whereas only minor morphological changes are observed. Conversely, chronic administration of DDC for several weeks results in severe morphological damage, characterized by hepatocellular ballooning, disruption of the intermediate filament cytoskeleton, and formation of Mallory-Denk bodies consisting predominantly of misfolded keratins, Sqstm1/p62, and heat shock proteins. To evaluate the mechanistic underpinnings for this dichotomy we dissected the time-course of DDC intoxication for up to 10 weeks. We determined body weight change, serum liver enzyme activities, morphologic alterations, induction of antioxidant response (heme oxygenase-1, HO-1, oxidative damage and ATP content in livers as well as respiration, oxidative damage and the presence and activity of HO-1 in endoplasmic reticulum and mitochondria (mtHO-1. Elevated serum liver enzyme activity and oxidative liver damage were already present at early intoxication stages without further subsequent increase. After 2 weeks of intoxication, mice had transiently lost 9% of their body weight, liver ATP-content was reduced to 58% of controls, succinate-driven respiration was uncoupled from ATP-production and antioxidant response was associated with the appearance of catalytically active mtHO-1. Oxidative damage was associated with both acute and chronic DDC toxicity whereas the onset of chronic intoxication was specifically associated with mitochondrial dysfunction which was maximal after 2 weeks of intoxication. At this transition stage, adaptive responses involving mtHO-1 were induced, indirectly leading to improved respiration and preventing further drop of ATP levels. Our observations clearly demonstrate principally different

  7. The modulatory effect of Moringa oleifera leaf extract on endogenous antioxidant systems and inflammatory markers in an acetaminophen-induced nephrotoxic mice model

    Directory of Open Access Journals (Sweden)

    Govindarajan Karthivashan

    2016-07-01

    Full Text Available N-Acetyl-p-Aminophenol (APAP, also known as acetaminophen, is the most commonly used over-the counter analgesic and antipyretic medication. However, its overdose leads to both liver and kidney damage. APAP-induced toxicity is considered as one of the primary causes of acute liver failure; numerous scientific reports have focused majorly on APAP hepatotoxicity. Alternatively, not many works approach APAP nephrotoxicity focusing on both its mechanisms of action and therapeutic exploration. Moringa oleifera (MO is pervasive in nature, is reported to possess a surplus amount of nutrients, and is enriched with several bioactive candidates including trace elements that act as curatives for various clinical conditions. In this study, we evaluated the nephro-protective potential of MO leaf extract against APAP nephrotoxicity in male Balb/c mice. A single-dose acute oral toxicity design was implemented in this study. Group 2, 3, 4 and 5 received a toxic dose of APAP (400 mg/kg of bw, i.p and after an hour, these groups were administered with saline (10 mL/kg, silymarin—positive control (100 mg/kg of bw, i.p, MO leaf extract (100 mg/kg of bw, i.p, and MO leaf extract (200 mg/kg bw, i.p respectively. Group 1 was administered saline (10 mL/kg during both the sessions. APAP-treated mice exhibited a significant elevation of serum creatinine, blood urea nitrogen, sodium, potassium and chloride levels. A remarkable depletion of antioxidant enzymes such as SOD, CAT and GSH-Px with elevated MDA levels has been observed in APAP treated kidney tissues. They also exhibited a significant rise in pro-inflammatory cytokines (TNF-α, IL-1β, IL-6 and decreased anti-inflammatory (IL-10 cytokine level in the kidney tissues. Disorganized glomerulus and dilated tubules with inflammatory cell infiltration were clearly observed in the histology of APAP treated mice kidneys. All these pathological changes were reversed in a dose-dependent manner after MO leaf extract

  8. The Possible Efficacy of Artichoke in Fluconazole Related Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Hüseyin Kurt

    2014-01-01

    Full Text Available Although fluconazole related hepatotoxicity (FRH is rare, mortal acute hepatic necrosis and jaundice were reported in immunocompromised states such as acquired immunodeficiency syndrome (AIDS and bone marrow transplant (BMT. We present a case of a patient with multiple sclerosis who developed hepatotoxicity with the use of a single 150 mg fluconazole tablet for fungal vaginitis, 10 days after methylprednisolone pulse treatment. Our patient’s alanine aminotransferase (ALT and aspartate aminotransferase (AST levels were decreased, 1200 U/L and 800 U/L, respectively, and bilirubin levels were consistent at 37 mg/dL. Artichoke which has anticholestatic and antioxidant properties was used by our patient. She consumed a 30 mg artichoke leaf extract tea 3 times a day. The bilirubin levels significantly declined at the end of the first week and all liver function tests were normalized within 2 months.

  9. Silymarin nanoparticle prevents paracetamol-induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Das S

    2011-06-01

    Full Text Available Suvadra Das, Partha Roy, Runa Ghosh Auddy, Arup MukherjeeDepartment of Chemical Technology, University of Calcutta, Kolkata, West Bengal, IndiaAbstract: Silymarin (Sm is a polyphenolic component extracted from Silybum marianum. It is an antioxidant, traditionally used as an immunostimulant, hepatoprotectant, and dietary supplement. Relatively recently, Sm has proved to be a valuable chemopreventive and a useful antineoplastic agent. Medical success for Sm is, however, constrained by very low aqueous solubility and associated biopharmaceutical limitations. Sm flavonolignans are also susceptible to ion-catalyzed degradation in the gut. Proven antihepatotoxic activity of Sm cannot therefore be fully exploited in acute chemical poisoning conditions like that in paracetamol overdose. Moreover, a synchronous delivery that is required for hepatic regeneration is difficult to achieve by itself. This work is meant to circumvent the inherent limitations of Sm through the use of nanotechnology. Sm nanoparticles (Smnps were prepared by nanoprecipitation in polyvinyl alcohol stabilized Eudragit RS100® polymer (Rohm Pharma GmbH, Darmstadt, Germany. Process parameter optimization provided 67.39% entrapment efficiency and a Gaussian particle distribution of average size 120.37 nm. Sm release from the nanoparticles was considerably sustained for all formulations. Smnps were strongly protective against hepatic damage when tested in a paracetamol overdose hepatotoxicity model. Nanoparticles recorded no animal death even when administered after an established paracetamol-induced hepatic necrosis. Preventing progress of paracetamol hepatic damage was traced for an efficient glutathione regeneration to a level of 11.3 µmol/g in hepatic tissue due to Smnps.Keywords: silymarin, paracetamol, nanoparticle, glutathione, mouse hepatotoxicity

  10. In vitro antioxidant and hepatoprotective potential of Azolla microphylla phytochemically synthesized gold nanoparticles on acetaminophen - induced hepatocyte damage in Cyprinus carpio L.

    Science.gov (United States)

    Kunjiappan, Selvaraj; Bhattacharjee, Chiranjib; Chowdhury, Ranjana

    2015-06-01

    The present study aims to evaluate the hepatoprotective and antioxidant effects of gold nanoparticles (GNaP) biosynthesized through the mediation of Azolla microphylla and A. microphylla extract on acetaminophen-induced hepatocyte damage in common carp fish (Cyprinus carpio L.). The gold nanoparticles (100, 150, 200 μg/ml) and A. microphylla extract powder (100, 200, 400 μg/ml) were added to the primary hepatocytes in different conditions: treatment I (before 12 mM acetaminophen), treatment II (after 12 mM acetaminophen), and treatment III (both before and after 12 mM acetaminophen), and incubated. Among these, control group treated with 12 mM acetaminophen produced significantly elevated levels (50-80%) of lactate dehydrogenase (LDH), catalase (CAT), glutamate oxalate transaminase (GOT), glutamate pyruvate transaminase (GPT), and malondialdehyde (MDA), and significantly decreased the levels (60-75%) of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Treatment with methanol extract of A. microphylla phytochemically biosynthesized gold nanoparticles (100, 150, 200 μg/ml) and A. microphylla methanol extract powder (100, 200, 400 μg/ml) significantly improved the viability of cells in a culture medium. It also significantly reduced the levels of LDH, CAT, GOT, GPT, and MDA, and significantly increased the levels of SOD and GSH-Px. In conclusion, gold nanoparticles biosynthesized through A. microphylla demonstrated effective hepatoprotective and antioxidant effects than methanol extract of A. microphylla.

  11. Unexpected paracetamol (acetaminophen) hepatotoxicity at standard dosage in two older patients: time to rethink 1 g four times daily?

    Science.gov (United States)

    Ging, Patricia; Mikulich, Olga; O'Reilly, Katherine M A

    2016-07-01

    We present two cases of acute hepatotoxicity associated with elevated paracetamol (acetaminophen) levels in older patients. Both patients were receiving a standard European dose of oral paracetamol (2 × 500 mg QDS) with no risk factors for slowed metabolism (weight paracetamol can be hepatotoxic. © The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  12. Identification of metabolites, clinical chemistry markers and transcripts associated with hepatotoxicity.

    Directory of Open Access Journals (Sweden)

    Andreas Buness

    Full Text Available Early and accurate pre-clinical and clinical biomarkers of hepatotoxicity facilitate the drug development process and the safety monitoring in clinical studies. We selected eight known model compounds to be administered to male Wistar rats to identify biomarkers of drug induced liver injury (DILI using transcriptomics, metabolite profiling (metabolomics and conventional endpoints. We specifically explored early biomarkers in serum and liver tissue associated with histopathologically evident acute hepatotoxicity. A tailored data analysis strategy was implemented to better differentiate animals with no treatment-related findings in the liver from animals showing evident hepatotoxicity as assessed by histopathological analysis. From the large number of assessed parameters, our data analysis strategy allowed us to identify five metabolites in serum and five in liver tissue, 58 transcripts in liver tissue and seven clinical chemistry markers in serum that were significantly associated with acute hepatotoxicity. The identified markers comprised metabolites such as taurocholic acid and putrescine (measured as sum parameter together with agmatine, classical clinical chemistry markers like AST (aspartate aminotransferase, ALT (alanine aminotransferase, and bilirubin, as well as gene transcripts like Igfbp1 (insulin-like growth factor-binding protein 1 and Egr1 (early growth response protein 1. The response pattern of the identified biomarkers was concordant across all types of parameters and sample matrices. Our results suggest that a combination of several of these biomarkers could significantly improve the robustness and accuracy of an early diagnosis of hepatotoxicity.

  13. Liver inflammation during monocrotaline hepatotoxicity

    International Nuclear Information System (INIS)

    Copple, Bryan L.; Ganey, Patricia E.; Roth, Robert A.

    2003-01-01

    Monocrotaline (MCT) is a pyrrolizidine alkaloid (PA) plant toxin that causes hepatotoxicity in humans and animals. Human exposure occurs from consumption of contaminated grains and herbal teas and medicines. Intraperitoneal injection (i.p.) of 300 mg/kg MCT in rats produced time-dependent hepatic parenchymal cell (HPC) injury beginning at 12 h. At this time, an inflammatory infiltrate consisting of neutrophils (PMNs) appeared in areas of hepatocellular injury, and activation of the coagulation system occurred. PMN accumulation was preceded by up-regulation of the PMN chemokines cytokine-induced neutrophil chemoattractant-1 (CINC-1) and macrophage inflammatory protein-2 (MIP-2) in the liver. The monocyte chemokine, monocyte chemoattractant protein-1 (MCP-1), was also upregulated. Inhibition of Kupffer cell function with gadolinium chloride (GdCl 3 ) significantly reduced CINC-1 protein in plasma after MCT treatment but had no effect on hepatic PMN accumulation. Since inflammation can contribute to either pathogenesis or resolution of tissue injury, we explored inflammatory factors as a contributor to MCT hepatotoxicity. To test the hypothesis that PMNs contribute to MCT-induced HPC injury, rats were depleted of PMNs with a rabbit anti-PMN serum prior to MCT treatment. Anti-PMN treatment reduced hepatic PMN accumulation by 80% but had no effect on MCT-induced HPC injury or activation of the coagulation system. To test the hypothesis that Kupffer cells and/or tumor necrosis factor-α (TNF-α) are required for MCT-induced HPC injury, rats were treated with either GdCl 3 to inhibit Kupffer cell function or pentoxifylline (PTX) to prevent synthesis of TNF-α. Neither treatment prevented MCT-induced HPC injury. Results from these studies suggest that PMNs, Kupffer cells and TNF-α are not critical mediators of MCT hepatotoxicity. Accordingly, although inflammation occurs in the liver after MCT treatment, it is not required for HPC injury and possibly occurs secondary to

  14. Lack of Direct Cytotoxicity of Extracellular ATP against Hepatocytes: Role in the Mechanism of Acetaminophen Hepatotoxicity

    NARCIS (Netherlands)

    Xie, Yuchao; Woolbright, Benjamin L.; Kos, Milan; McGill, Mitchell R.; Dorko, Kenneth; Kumer, Sean C.; Schmitt, Timothy M.; Jaeschke, Hartmut

    2015-01-01

    Acetaminophen (APAP) hepatotoxicity is a major cause of acute liver failure in many countries. Mechanistic studies in mice and humans have implicated formation of a reactive metabolite, mitochondrial dysfunction and oxidant stress as critical events in the pathophysiology of APAP-induced liver cell

  15. A Prominent Role of Interleukin-18 in Acetaminophen-Induced Liver Injury Advocates Its Blockage for Therapy of Hepatic Necroinflammation

    Directory of Open Access Journals (Sweden)

    Malte Bachmann

    2018-02-01

    Full Text Available Acetaminophen [paracetamol, N-acetyl-p-aminophenol (APAP]-induced acute liver injury (ALI not only remains a persistent clinical challenge but likewise stands out as well-characterized paradigmatic model of drug-induced liver damage. APAP intoxication associates with robust hepatic necroinflammation the role of which remains elusive with pathogenic but also pro-regenerative/-resolving functions being ascribed to leukocyte activation. Here, we shine a light on and put forward a unique role of the interleukin (IL-1 family member IL-18 in experimental APAP-induced ALI. Indeed, amelioration of disease as previously observed in IL-18-deficient mice was further substantiated herein by application of the IL-18 opponent IL-18-binding protein (IL-18BPd:Fc to wild-type mice. Data altogether emphasize crucial pathological action of this cytokine in APAP toxicity. Adding recombinant IL-22 to IL-18BPd:Fc further enhanced protection from liver injury. In contrast to IL-18, the role of prototypic pro-inflammatory IL-1 and tumor necrosis factor-α is controversially discussed with lack of effects or even protective action being repeatedly reported. A prominent detrimental function for IL-18 in APAP-induced ALI as proposed herein should relate to its pivotal role for hepatic expression of interferon-γ and Fas ligand, both of which aggravate APAP toxicity. As IL-18 serum levels increase in patients after APAP overdosing, targeting IL-18 may evolve as novel therapeutic option in those hard-to-treat patients where standard therapy with N-acetylcysteine is unsuccessful. Being a paradigmatic experimental model of ALI, current knowledge on ill-fated properties of IL-18 in APAP intoxication likewise emphasizes the potential of this cytokine to serve as therapeutic target in other entities of inflammatory liver diseases.

  16. [Hepatox: database on hepatotoxic drugs].

    Science.gov (United States)

    Quinton, A; Latry, P; Biour, M

    1993-01-01

    Hepatox is a data base on the hepatotoxic drugs file published every year in Gastroentérologie Clinique et Biologique. The program was developed under Omnis 7 for Apple computers, and under Visual Basic Professional Toolkit and Code Base for IBM PC and compatibles computers. The data base includes forms of 866 drugs identified by their approved name and those of their 1,300 corresponding proprietary names in France; drugs are distributed among 104 pharmacological classes. It is possible to have instantaneously access to the card of a drug identified by its approved name. Acceding to a drug identified by its proprietary name gives a list of the approved name of its components; going from a name of this list to the correspondent card of hepatoxicity is immediate. It is easy to extract lists of drugs responsible of a type of hepatic injury, and a table of types of hepatic injuries induced by the drugs of a pharmacological class.

  17. Hepatotoxicity and the present herbal hepatoprotective scenario

    OpenAIRE

    Priyankar Dey; Manas Ranjan Saha; Arnab Sen

    2013-01-01

    Most of the metabolic and physiological processes of our body as well as the detoxification of various drugs and xenobiotic chemicals occur in the liver. During this detoxification process, the reactive chemical intermediates damage the liver severely. There are several commercially available drugs, consumption of which results in idiosyncratic drug reaction mediated hepatotoxicity. Drug induced hepatotoxicity is a burning problem in this regard and several drugs are withdrawn from the market...

  18. Accuracy of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity in modified-release paracetamol overdose.

    Science.gov (United States)

    Wong, Anselm; Sivilotti, Marco L A; Graudins, Andis

    2017-06-01

    The paracetamol-aminotransferase multiplication product (APAP × ALT) is a risk predictor of hepatotoxicity that is somewhat independent of time and type of ingestion. However, its accuracy following ingestion of modified-release formulations is not known, as the product has been derived and validated after immediate-release paracetamol overdoses. The aim of this retrospective cohort study was to evaluate the accuracy of the multiplication product to predict hepatotoxicity in a cohort of patients with modified-release paracetamol overdose. We assessed all patients with modified-release paracetamol overdose presenting to our hospital network from October 2009 to July 2016. Ingestion of a modified-release formulation was identified by patient self-report or retrieval of the original container. Hepatotoxicity was defined as peak alanine aminotransferase ≥1000 IU/L, and acute liver injury (ALI) as a doubling of baseline ALT to more than 50 IU/L. Of 1989 paracetamol overdose presentations, we identified 73 modified-release paracetamol exposures treated with acetylcysteine. Five patients developed hepatotoxicity, including one who received acetylcysteine within eight hours of an acute ingestion. No patient with an initial multiplication product paracetamol overdose treated with acetylcysteine, the paracetamol-aminotransferase multiplication product demonstrated similar accuracy and temporal profile to previous reports involving mostly immediate-release formulations. Above a cut-point of 10,000 mg/L × IU/L, it was very strongly associated with the development of acute liver injury and hepatotoxicity, especially when calculated more than eight hours post-ingestion. When below 1500 mg/L × IU/L the likelihood of developing hepatotoxicity was very low. Persistently high serial multiplication product calculations were associated with the greatest risk of hepatotoxicity.

  19. Herbal Hepatotoxicity: Clinical Characteristics and Listing Compilation

    Directory of Open Access Journals (Sweden)

    Christian Frenzel

    2016-04-01

    Full Text Available Herb induced liver injury (HILI and drug induced liver injury (DILI share the common characteristic of chemical compounds as their causative agents, which were either produced by the plant or synthetic processes. Both, natural and synthetic chemicals are foreign products to the body and need metabolic degradation to be eliminated. During this process, hepatotoxic metabolites may be generated causing liver injury in susceptible patients. There is uncertainty, whether risk factors such as high lipophilicity or high daily and cumulative doses play a pathogenetic role for HILI, as these are under discussion for DILI. It is also often unclear, whether a HILI case has an idiosyncratic or an intrinsic background. Treatment with herbs of Western medicine or traditional Chinese medicine (TCM rarely causes elevated liver tests (LT. However, HILI can develop to acute liver failure requiring liver transplantation in single cases. HILI is a diagnosis of exclusion, because clinical features of HILI are not specific as they are also found in many other liver diseases unrelated to herbal use. In strikingly increased liver tests signifying severe liver injury, herbal use has to be stopped. To establish HILI as the cause of liver damage, RUCAM (Roussel Uclaf Causality Assessment Method is a useful tool. Diagnostic problems may emerge when alternative causes were not carefully excluded and the correct therapy is withheld. Future strategies should focus on RUCAM based causality assessment in suspected HILI cases and more regulatory efforts to provide all herbal medicines and herbal dietary supplements used as medicine with strict regulatory surveillance, considering them as herbal drugs and ascertaining an appropriate risk benefit balance.

  20. Incidence of antituberculosis-drug-induced hepatotoxicity and associated risk factors among tuberculosis patients in Dawro Zone, South Ethiopia: A cohort study

    OpenAIRE

    Wondwossen Abera,; Waqtola Cheneke,; Gemeda Abebe,

    2016-01-01

    Background: Antituberculosis drugs cause hepatotoxicity in some individuals leading to acute liver failure, which results in death. Such phenomena limit the clinical use of drugs, contributing to treatment failure that possibly causes drug resistance. Furthermore, associated risk factors for the development of antituberculosis-drug-induced hepatotoxicity (anti-TB-DIH) are found to be controversial among different study findings. Methods: A prospective cohort study was conducted from May 20...

  1. Acetaminophen hepatotoxicity in mice: Effect of age, frailty and exposure type

    Science.gov (United States)

    Kane, Alice E.; Mitchell, Sarah J.; Mach, John; Huizer-Pajkos, Aniko; McKenzie, Catriona; Jones, Brett; Cogger, Victoria; Le Couteur, David G.; de Cabo, Rafael; Hilmer, Sarah N.

    2018-01-01

    Acetaminophen is a commonly used analgesic that can cause severe hepatotoxicity in overdose. Despite old age and frailty being associated with extensive and long-term utilization of acetaminophen and a high prevalence of adverse drug reactions, there is limited information on the risks of toxicity from acetaminophen in old age and frailty. This study aimed to assess changes in the risk and mechanisms of hepatotoxicity from acute, chronic and sub-acute acetaminophen exposure with old age and frailty in mice. Young and old male C57BL/6 mice were exposed to either acute (300 mg/kg via oral gavage), chronic (100 mg/kg/day in diet for six weeks) or sub-acute (250 mg/kg, t.i.d., for three days) acetaminophen, or saline control. Pre-dosing mice were scored for the mouse clinical frailty index, and after dosing serum and liver tissue were collected for assessment of toxicity and mechanisms. There were no differences with old age or frailty in the degree of hepatotoxicity induced by acute, chronic or subacute acetaminophen exposure as assessed by serum liver enzymes and histology. Age-related changes in the acetaminophen toxicity pathways included increased liver GSH concentrations, increased NQO1 activity and an increased pro- and anti-inflammatory response to acetaminophen in old age. Frailty-related changes included a negative correlation between frailty index and serum protein, albumin and ALP concentrations for some mouse groups. In conclusion, although there were changes in some pathways that would be expected to influence susceptibility to acetaminophen toxicity, there was no overall increase in acetaminophen hepatotoxicity with old age or frailty in mice. PMID:26615879

  2. Hepatotoxicity in hyperthyroid patient after consecutive methimazole and propylthiouracil therapies

    Directory of Open Access Journals (Sweden)

    Fernando Gomez-Peralta

    2018-01-01

    Full Text Available Methimazole (MMI and propylthiouracil (PTU are widely used antithyroid drugs (ATD that have been approved for the treatment of hyperthyroidism. Hepatotoxicity may be induced by these drugs, though they exert dissimilar incidence rates of hepatotoxicity and, possibly, with different underlying pathogenic mechanisms. We report the case of a 55-year-old woman with no relevant medical history diagnosed with hyperthyroidism due to Graves’ disease, who developed two episodes of acute hepatitis concurrent with the consecutive administration of two different ATDs, first MMI and then PTU. Given the impossibility of administering ATDs, it was decided to perform a total thyroidectomy because the patient was found to be euthyroid at that point. Pathological anatomy showed diffuse hyperplasia and a papillary thyroid microcarcinoma of 2 mm in diameter. Subsequent clinical check-ups were normal. This case suggests the importance of regular monitoring of liver function for hyperthyroid patients. Due to the potential severity of this side effect, it is recommended to determine baseline liver function prior to initiation of treatment.

  3. [Hepatotoxicity associated with the use of Herbalife].

    Science.gov (United States)

    Jóhannsson, Magnús; Ormarsdóttir, Sif; Olafsson, Sigurdur

    2010-03-01

    Many herbal products are known to be hepatotoxic. In a recent survey in Iceland concerning adverse reactions related to herbal medicines, Herbalife products were implicated in the majority of the reported cases of hepatotoxicity. The clinical presentations of five cases of Herbalife related liver injury during the period of 1999-2008 are analysed. Causality was assessed by using the WHO-UMC system for causality assessment and the RUCAM method. Of the five cases there were four females and one male; median age was 46 years (range 29-78). Herbalife had been used for 1 to 7 months prior to presentation. Four patients presented with a hepatocellular and one with a cholestatic reaction. Median values were for bilirubin 190 micromol/L (range: 26-311; ref. Herbalife products. Hepatotoxicity due to herbal remedies is an important differential diagnosis in the diagnostic work-up of liver injury.

  4. Lycopene inhibits reactive oxygen species production in SK-Hep-1 cells and attenuates acetaminophen-induced liver injury in C57BL/6 mice.

    Science.gov (United States)

    Bandeira, Ana Carla Balthar; da Silva, Talita Prato; de Araujo, Glaucy Rodrigues; Araujo, Carolina Morais; da Silva, Rafaella Cecília; Lima, Wanderson Geraldo; Bezerra, Frank Silva; Costa, Daniela Caldeira

    2017-02-01

    Our aim was to investigate the antioxidant potential of lycopene in different experimental liver models: in vitro, to evaluate the influence of lycopene on reactive oxygen species (ROS) production mediated by the PKC pathway and in vivo, to evaluate the protective effects of lycopene in an experimental model of hepatotoxicity. The in vitro study assessed the lycopene antioxidant potential by the quantification of ROS production in SK-Hep-1 cells unstimulated or stimulated by an activator of the PKC pathway. The role of NADPH oxidase was evaluated by measuring its inhibition potential using an inhibitor of this enzyme. In the in vivo study, male C57BL/6 mice received lycopene (10 or 100 mg/kg by oral gavage) and 1 h later, acetaminophen (APAP) (500 mg/kg) was administrated. Lycopene decreased ROS production in SK-Hep-1 cells through inhibition of NADPH oxidase, brought about in the PKC pathway. Lycopene improved hepatotoxicity acting as an antioxidant, reduced GSSG and regulated tGSH and CAT levels, reduced oxidative damage primarily by decreasing protein carbonylation, promoted the downregulation of MMP-2 and reduced areas of necrosis improving the general appearance of the lesion in C57BL/6 mice. Lycopene is a natural compound that was able to inhibit the production of ROS in vitro and mitigate the damage caused by APAP overdose in vivo. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. Hepatotoxicity with antituberculosis drugs: the risk factors

    International Nuclear Information System (INIS)

    Mahmood, K.; Samo, A.H.; Jairamani, K.L.; Talib, A.

    2007-01-01

    To assess the severity and frequency of hepatotoxicity caused by different antituberculosis (ATT) drugs and to evaluate whether concurrence of risk factors influence the antituberculosis drug induced hepatotoxicity. This prospective cohort study was conducted in Medical Unit-V and OPD department of Civil Hospital Karachi from July 2004 to July 2005. A total of 339 patients diagnosed of active tuberculosis infection with normal pretreatment liver function were monitored clinically as well as biochemically. Their data were collected on proforma and patients were treated with Isoniazid, Rifampicin and Pyrazinamide. Duration after which derangement in function, if any, occurred and time taken for normalization was noted. Treatment was altered as needed, with exclusion of culprit drug. Finally data was analyzed by SPSS version 10.0. ATT induced hepatotoxicity was seen in 67 (19.76%) out of 339 patients. Females were more affected as compared to males (26.3% vs. 19.7%). BMI (kg/m2) of 91% of diseased group were less than 18.5 (p<0.01) most of them were anemic having low albumin level suggestive of lean body mass. Hepatotoxicity was more severe in AFB smear positive patients. Concomitant use of alcohol, paracetamol and low serum cholesterol were proved as predisposing factors. Isoniazid (37 patients (55.21%), p<0.01) was the main culprit followed by Rifampicin (23 patients, 34.21%) and Pyrazinamide (7 patients, 10.5%). Most of the patients (61%) developed the hepatotoxicity within two weeks of starting antituberculosis therapy with mild to moderate alteration in ALT and AST. ATT-induced hepatitis is significantly more frequent and more severe in patients with hepatotoxicity risk factors. (author)

  6. Increased Expression of Cytotoxic T-Lymphocyte-Associated Protein 4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure

    DEFF Research Database (Denmark)

    Khamri, Wafa; Abeles, Robin D; Hou, Tie Zheng

    2017-01-01

    , hepatic sinusoidal endothelial cells, and biliary epithelial cells from healthy or diseased liver tissues. We also measured levels of soluble B7 serum samples from patients and controls, and mice with acetaminophen-induced liver injury using enzyme-linked immunosorbent assays. RESULTS: Peripheral blood...... mice with acetaminophen-induced liver injury contained high levels of soluble B7 compared to sera from mice without liver injury. Plasma exchange reduced circulating levels of soluble B7 in patients with ALF and expression of CTLA4 on T cells. CONCLUSIONS: Peripheral CD4+ T cells from patients with ALF......BACKGROUND & AIMS: Patients with acute liver failure (ALF) have defects in innate immune responses to microbes (immune paresis) and are susceptible to sepsis. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), which interacts with the membrane receptor B7 (also called CD80 and CD86...

  7. DILI (drug induced liver injury in a 9-month-old infant: a rare case of phenobarbital-induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Anna Paola Pinna

    2013-04-01

    Full Text Available Phenobarbital is one of the most commonly prescribed antiepileptic drugs in childhood, but it can rarely cause serious adverse effects, such as hepatotoxicity that includes a broad clinical spectrum (from isolate hypertransaminasemia to acute liver failure. We describe a case of DILI in a 9-month-old infant caused by chronic therapy with phenobarbital.

  8. Enhancement of acetaminophen overdosage-induced hepatotoxicity ...

    African Journals Online (AJOL)

    paracetamol) overdosage-induced hepatotoxicity in three groups of albino Wistar rats. Administration of the minimum toxic dose of paracetamol (150mg/kg body weight) to animals (group II) produced significantly (P≤0.05) higher levels of alanine ...

  9. Hepatoprotective effect of fermented ginseng and its major constituent compound K in a rat model of paracetamol (acetaminophen)-induced liver injury.

    Science.gov (United States)

    Igami, Kentaro; Shimojo, Yosuke; Ito, Hisatomi; Miyazaki, Toshitsugu; Kashiwada, Yoshiki

    2015-04-01

    This work aimed at evaluating the effect of fermented ginseng (FG) and fermented red ginseng (FRG) against rat liver injury caused by paracetamol (acetaminophen (APAP)). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum and histopathological changes in the liver were analysed to determine the degree of liver injury. Deoxyribonucleic acid (DNA) microarray analysis was performed to compare gene expression levels altered in the rat livers. Phosphorylated Jun-N-terminal kinase (JNK) in human hepatocellular carcinoma (HepG2) cells were detected using western blot analysis to investigate the anti-inflammatory activity of compound K. Pretreatment with FG, containing compound K at high concentration, attenuated AST as well as ALT levels in rats, while no obvious effect was observed in the group that received FRG, whose content of compound K was lower than that of FG. In addition, the results of our histopathological analysis were consistent with changes in the serum biochemical analysis. DNA microarray analysis indicated that JNK- and glutathione S-transferase (GST)-related genes were involved in the hepatotoxicity. Notably, compound K, a major ginsenoside in FG, inhibited the phosphorylation of JNK in HepG2 cells. FG was shown to possess hepatoprotective activity against paracetamol (APAP)-induced liver injury better than FRG. Compound K might play an important role for an anti-inflammatory activity of FG by inhibiting JNK signalling in the liver. © 2014 Royal Pharmaceutical Society.

  10. Alleviative effects from boswellic acid on acetaminophen-induced hepatic injury - Corrected and republished from: Biomedicine (Taipei). 2016 Jun; 6 (2): 9. doi: 10.7603/s40681-016-0009-1PMCID: PMC4864770.

    Science.gov (United States)

    Chen, Lung-Che; Hu, Li-Hong; Yin, Mei-Chin

    2017-06-01

    Protective effects of boswellic acid (BA) against acetaminophen (APAP)-induced hepatotoxicity in Balb/ cA mice were examined. BA, at 0.05 or 0.1%, was supplied for 4 weeks. Acute liver injury was induced by APAP treatment. Results showed that BA intake increased hepatic BA bioavailability. APAP treatment decreased glutathione (GSH) level, increased reactive oxygen species (ROS) and oxidized glutathione (GSSG) production; and lowered activity and protein expression of glutathione reductase (GR) and heme oxygenase (HO)-1 in liver. BA intake at both doses alleviated subsequent APAP-induced oxidative stress by retaining GSH content, decreasing ROS and GSSG formations, reserving activity and expression of GR and HO-1 in liver, and lowering hepatic cytochrome P450 2E1 activity and expression. APAP treatment enhanced hepatic levels of interleukin-6, tumor necrosis factor-alpha and monocyte chemoattractant protein-1. BA pre-intake diminished APAP-induced release of those inflammatory cytokines and chemokines. APAP up-regulated hepatic protein expression of toll-like receptor (TLR)-3, TLR-4, MyD88, nuclear factor kappa B (NF-κB) p50, NF-κB p65 and JNK. BA pre-intake at both doses suppressed the expression of NF-κB p65 and p-JNK, and only at 0.1% down-regulated hepatic TLR-3, TLR-4 and MyD88 expression. APAP led to obvious foci of inflammatory cell infiltration in liver, determined by H&E stain. BA intake at both doses attenuated hepatic inflammatory infiltration. These findings support that boswellic acid is a potent hepato-protective agent. © Author(s) 2017. This article is published with open access by China Medical University.

  11. Chemoprotective effect of insulin-like growth factor I against acetaminophen-induced cell death in Chang liver cells via ERK1/2 activation

    International Nuclear Information System (INIS)

    Hwang, Hye-Jung; Kwon, Mi-Jin; Nam, Taek-Jeong

    2007-01-01

    The insulin-like growth factor (IGF) system and type-I IGF receptor (IGF-IR) signaling are involved in protecting against chemotherapeutic drug-induced cell death in human hepatoma cells. Acetaminophen (AAP) hepatotoxicity is the leading cause of liver failure, and the prevention of AAP-induced cell death has been the focus of many studies. We determined whether IGF-I could protect against AAP-induced cell death in Chang liver cells and investigated the protective mechanism. Based on the results of MTS assays, LDH release assays, Hoechst 33342 cell staining, and DNA fragmentation experiments, AAP induced cell death in a dose-dependent manner. According to Western blot analysis, treatment with AAP increased the level of poly(ADP-ribose) polymerase (PARP) fragments in cells compared with that in control cells; however, caspase-3, a critical signaling molecule in apoptosis, was not activated after AAP overdose. Moreover, combined treatment with AAP and IGF-I inhibited PARP cleavage, which was consistent with the ability of IGF-I to restore the level of glutathione (GSH) and cell viability in GSH and MTS assays, respectively. We investigated whether the protective effect of IGF-I against AAP cytotoxicity is related to the extracellular signal-related kinase ERK1/2, which is generally activated by mitogenic and proliferative stimuli such as growth factors. Compared with AAP treatment alone, IGF-I and AAP co-treatment increased ERK1/2 phosphorylation but inhibited PARP cleavage. Thus ERK1/2 activation is instrumental in the protective effect of IGF-I against AAP-induced cell death in Chang liver cells

  12. Globular adiponectin protects rat hepatocytes against acetaminophen-induced cell death via modulation of the inflammasome activation and ER stress: Critical role of autophagy induction.

    Science.gov (United States)

    Kim, Eun Hye; Park, Pil-Hoon

    2018-05-24

    Acetaminophen (APAP) overdose treatment causes severe liver injury. Adiponectin, a hormone predominantly produced by adipose tissue, exhibits protective effects against APAP-induced hepatotoxicity. However, the underlying mechanisms are not clearly understood. In the present study, we examined the protective effect of globular adiponectin (gAcrp) on APAP-induced hepatocyte death and its underlying mechanisms. We found that APAP (2 mM)-induced hepatocyte death was prevented by inhibition of the inflammasome. In addition, treatment with gAcrp (0.5 and 1 μg/ml) inhibited APAP-induced activation of the inflammasome, judged by suppression of interleukin-1β maturation, caspase-1 activation, and apoptosis-associated speck-like protein (ASC) speck formation, suggesting that protective effects of gAcrp against APAP-induced hepatocyte death is mediated via modulation of the inflammasome. APAP also induced ER stress and treatment with tauroursodeoxycholic acid (TUDCA), an ER chaperone and inhibitor of ER stress, abolished APAP-induced inflammasomes activation, implying that ER stress acts as signaling event leading to the inflammasome activation in hepatocytes stimulated with APAP. Moreover, gAcrp significantly suppressed APAP-induced expression of ER stress marker genes. Finally, the modulatory effects of gAcrp on ER stress and inflammasomes activation were abrogated by treatment with autophagy inhibitors, while an autophagy inducer (rapamycin) suppressed APAP-elicited ER stress, demonstrating that autophagy induction plays a crucial role in the suppression of APAP-induced inflammasome activation and ER stress by gAcrp. Taken together, these results indicate that gAcrp protects hepatocytes against APAP-induced cell death by modulating ER stress and the inflammasome activation, at least in part, via autophagy induction. Copyright © 2018. Published by Elsevier Inc.

  13. Gemfibrozil hepatotoxicity: a case report.

    Science.gov (United States)

    Domínguez Tordera, Patricia; Comellas Alabern, José Francisco; Ronda Rivero, Félix

    2011-10-01

    A 55-year-old woman was admitted to our hospital for management of thoracic trauma and bone fractures. One month after admission she started to receive gemfibrozil for hypertriglyceridemia. In the second month of admission, the patient complained of nausea and malaise. Laboratory value showed an acute hepatitis with raised AST, ALT. The abdominal ultrasound scan was normal, and viral serologic tests were negative. Gemfibrozil was discontinued and in a few days AST and ALT levels returned to normal. Gemfibrozil-induced hepatitis is a rare event but should be considered in the differential diagnoses of hepatitis in which no other obvious alternative cause is found.

  14. The current state of serum biomarkers of hepatotoxicity.

    Science.gov (United States)

    Ozer, Josef; Ratner, Marcia; Shaw, Martin; Bailey, Wendy; Schomaker, Shelli

    2008-03-20

    The level of serum alanine aminotransferase (ALT) activity reflects damage to hepatocytes and is considered to be a highly sensitive and fairly specific preclinical and clinical biomarker of hepatotoxicity. However, an increase in serum ALT activity level has also been associated with other organ toxicities, thus, indicating that the enzyme has specificity beyond liver in the absence of correlative histomorphologic alteration in liver. Thus, unidentified non-hepatic sources of serum ALT activity may inadvertently influence the decision of whether to continue development of a novel pharmaceutical compound. To assess the risk of false positives due to extraneous sources of serum ALT activity, additional biomarkers are sought with improved specificity for liver function compared to serum ALT activity alone. Current published biomarker candidates are reviewed herein and compared with ALT performance in preclinical and on occasion, clinical studies. An examination of the current state of hepatotoxic biomarkers indicates that serum F protein, arginase I, and glutathione-S-transferase alpha (GSTalpha) levels, all measured by ELISA, may show utility, however, antibody availability and high cost per run may present limitations to widespread applicability in preclinical safety studies. In contrast, the enzymatic markers sorbitol dehydrogenase, glutamate dehydrogenase, paraxonase, malate dehydrogenase, and purine nucleoside phosphorylase are all readily measured by photometric methods and use reagents that work across preclinical species and humans and are commercially available. The published literature suggests that these markers, once examined collectively in a large qualification study, could provide additional information relative to serum ALT and aspartate aminotransferase (AST) values. Since these biomarkers are found in the serum/plasma of treated humans and rats, they have potential to be utilized as bridging markers to monitor acute drug-induced liver injury in

  15. The current state of serum biomarkers of hepatotoxicity

    International Nuclear Information System (INIS)

    Ozer, Josef; Ratner, Marcia; Shaw, Martin; Bailey, Wendy; Schomaker, Shelli

    2008-01-01

    The level of serum alanine aminotransferase (ALT) activity reflects damage to hepatocytes and is considered to be a highly sensitive and fairly specific preclinical and clinical biomarker of hepatotoxicity. However, an increase in serum ALT activity level has also been associated with other organ toxicities, thus, indicating that the enzyme has specificity beyond liver in the absence of correlative histomorphologic alteration in liver. Thus, unidentified non-hepatic sources of serum ALT activity may inadvertently influence the decision of whether to continue development of a novel pharmaceutical compound. To assess the risk of false positives due to extraneous sources of serum ALT activity, additional biomarkers are sought with improved specificity for liver function compared to serum ALT activity alone. Current published biomarker candidates are reviewed herein and compared with ALT performance in preclinical and on occasion, clinical studies. An examination of the current state of hepatotoxic biomarkers indicates that serum F protein, arginase I, and glutathione-S-transferase alpha (GSTα) levels, all measured by ELISA, may show utility, however, antibody availability and high cost per run may present limitations to widespread applicability in preclinical safety studies. In contrast, the enzymatic markers sorbitol dehydrogenase, glutamate dehydrogenase, paraxonase, malate dehydrogenase, and purine nucleoside phosphorylase are all readily measured by photometric methods and use reagents that work across preclinical species and humans and are commercially available. The published literature suggests that these markers, once examined collectively in a large qualification study, could provide additional information relative to serum ALT and aspartate aminotransferase (AST) values. Since these biomarkers are found in the serum/plasma of treated humans and rats, they have potential to be utilized as bridging markers to monitor acute drug-induced liver injury in early

  16. Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity

    Science.gov (United States)

    Massart, Julie; Begriche, Karima; Moreau, Caroline; Fromenty, Bernard

    2017-01-01

    Background Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD. Aim The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity. For this purpose, we performed a data-mining analysis using different queries including drug-induced liver injury (or DILI), drug-induced hepatotoxicity, fatty liver, nonalcoholic fatty liver disease (or NAFLD), steatosis and obesity. The main data from the collected articles are reported in this review and when available, some pathophysiological hypotheses are put forward. Relevance for patients Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen, halothane, methotrexate, rosiglitazone, stavudine and tamoxifen. For some of these drugs, experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD. Other drugs such as pentoxifylline, phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not. Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes, hyperlipidemia and coronary heart disease, it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening

  17. Toxicoproteomic assessment of liver responses to acute pyrrolizidine alkaloid intoxication in rats.

    Science.gov (United States)

    Li, Yan-Hong; Tai, William Chi-Shing; Khan, Imran; Lu, Cheng; Lu, Yao; Wong, Wing-Yan; Chan, Wood-Yee; Wendy Hsiao, Wen-Luan; Lin, Ge

    2018-04-03

    A toxicoproteomic study was performed on liver of rats treated with retrorsine (RTS), a representative hepatotoxic pyrrolizidine alkaloid at a toxic dose (140 mg/kg) known to cause severe acute hepatotoxicity. By comparing current data with our previous findings in mild liver lesions of rats treated with a lower dose of RTS, seven proteins and three toxicity pathways of vascular endothelial cell death, which was further verified by observed sinusoidal endothelial cell losses, were found uniquely associated with retrorsine-induced hepatotoxicity. This toxicoproteomic study of acute pyrrolizidine alkaloid intoxication lays a foundation for future investigation to delineate molecular mechanisms of pyrrolizidine alkaloid-induced hepatotoxicity.

  18. Accuracy of the paracetamol-aminotransferase product to predict hepatotoxicity in paracetamol overdose treated with a 2-bag acetylcysteine regimen.

    Science.gov (United States)

    Wong, Anselm; Sivilotti, Marco L A; Gunja, Naren; McNulty, Richard; Graudins, Andis

    2018-03-01

    Paracetamol concentration is a highly accurate risk predictor for hepatotoxicity following overdose with known time of ingestion. However, the paracetamol-aminotransferase multiplication product can be used as a risk predictor independent of timing or ingestion type. Validated in patients treated with the traditional, "three-bag" intravenous acetylcysteine regimen, we evaluated the accuracy of the multiplication product in paracetamol overdose treated with a two-bag acetylcysteine regimen. We examined consecutive patients treated with the two-bag regimen from five emergency departments over a two-year period. We assessed the predictive accuracy of initial multiplication product for the primary outcome of hepatotoxicity (peak alanine aminotransferase ≥1000IU/L), as well as for acute liver injury (ALI), defined peak alanine aminotransferase ≥2× baseline and above 50IU/L). Of 447 paracetamol overdoses treated with the two-bag acetylcysteine regimen, 32 (7%) developed hepatotoxicity and 73 (16%) ALI. The pre-specified cut-off points of 1500 mg/L × IU/L (sensitivity 100% [95% CI 82%, 100%], specificity 62% [56%, 67%]) and 10,000 mg/L × IU/L (sensitivity 70% [47%, 87%], specificity of 97% [95%, 99%]) were highly accurate for predicting hepatotoxicity. There were few cases of hepatotoxicity irrespective of the product when acetylcysteine was administered within eight hours of overdose, when the product was largely determined by a high paracetamol concentration but normal aminotransferase. The multiplication product accurately predicts hepatotoxicity when using a two-bag acetylcysteine regimen, especially in patients treated more than eight hours post-overdose. Further studies are needed to assess the product as a method to adjust for exposure severity when testing efficacy of modified acetylcysteine regimens.

  19. A review of the evidence concerning hepatic glutathione depletion and susceptibility to hepatotoxicity after paracetamol overdose

    Directory of Open Access Journals (Sweden)

    Kalsi SS

    2011-12-01

    Full Text Available Sarbjeet S Kalsi1,2, Paul I Dargan2–4, W Stephen Waring5, David M Wood2–41Emergency Department, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 2Clinical Toxicology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 3King’s Health Partners, London, UK; 4King’s College London, London, UK; 5York Teaching Hospital NHS Foundation Trust, York, UKAbstract: Paracetamol (acetaminophen poisoning is common throughout the world. The management of nonstaggered (acute paracetamol overdose is based on the plasma paracetamol concentration plotted on a treatment nomogram. In the UK there are two treatment lines on this nomogram, with the lower treatment line used for individuals felt to be at ‘high risk’ of paracetamol-related hepatotoxicity either as a result of induction of cytochrome P450 isoenzymes or reduction of intrahepatic glutathione. In this article we review the risk factors that, in current guidelines, are felt to increase risk due to a reduction in intrahepatic glutathione concentrations. Based on our review of the published literature, we feel that cystic fibrosis, acute viral illness, malnutrition, and eating disorders such as anorexia nervosa are likely to be associated with reduction in intrahepatic glutathione concentrations, and that this risk is likely to be related to malnutrition secondary to the disease. Chronic hepatitis C infection is also associated with reduced glutathione concentrations, although this appears to be independent of any associated malnutrition. Ageing and acute fasting are not associated with an increased risk of paracetamol-related hepatotoxicity due to reductions in glutathione concentrations. Finally, the evidence for HIV infection is inconclusive, particularly as the majority of studies were conducted in the pre-anti-viral treatment (HAART era; however it is likely that patients with symptomatic HIV/AIDS have reduced glutathione concentrations due to associated malnutrition. Although

  20. [Screening of hepatotoxicity fraction of Genkwa Flos and study on UPLC fingerprint of hepatotoxicity fraction].

    Science.gov (United States)

    Yuan, Yang; Geng, Lu-Lu; Zhuang, He-Fei; Meng, Xia; Peng, Ying; Bi, Kai-Shun; Chen, Xiao-Hui

    2013-01-01

    To look for the active fraction of ethanol extract of Genkwa Flos (EGF) induced hepatotoxicity and develop an UPLC fingerprint of the active fraction. Target fraction of EGF induced hepatotoxicity was guided by the serum biochemical and histopathology methods. The UPLC method was applied to establish the chromatographic fingerprint. The separation was achieved on a BEH C18 column (2.1 mm x 50 mm, 1.7 microm) with a mobile phase consisting of acetonitrile and water containing 0.05% phosphate acid running gradient elution. The detection was carried out at 210 nm and the analysis was finished within 10 min. The chloroform phase of EGF could be responsible for the hepatotoxicity of this herb. The common mode of the UPLC fingerprint was set up under the established condition. There were 17 common peaks in fourteen batches of herbs, eight of which were identified, and the similar degrees of the fourteen batches to the common mode were between 0.890-0.999. It is easy to locate the chloroform extraction of EGF with hepatotoxicity. And the UPLC fingerprint was developed for the above fraction, which could provide valuable references for safe and effective clinical use of EGF.

  1. An Evaluation of Hepatotoxicity in Breast Cancer Patients Receiving ...

    African Journals Online (AJOL)

    Background: Hepatic dysfunction in the cancer unit has a significant impact on patient outcomes. The therapeutic application of anthracycline antibiotics are limited by side‑effects mainly myelosuppression, chronic cardiotoxicity, and hepatotoxicity. Aim: To assess the risk of Hepatotoxicity in breast cancer patients receiving ...

  2. Antituberculosis drugs and hepatotoxicity among hospitalized patients in Jos, Nigeria

    Directory of Open Access Journals (Sweden)

    Samson E Isa

    2016-01-01

    Conclusion: Hepatotoxicity due to first-line anti-TBs, whether based on clinical features alone or backed by liver chemistry, is common among hospitalized patients in our environment. Studies to determine the predictors of hepatotoxicity to guide clinical interventions aimed at the prevention or timely identification of cases are needed.

  3. [Constitutional syndrome associated to metformin induced hepatotoxicity].

    Science.gov (United States)

    de la Poza Gómez, Gema; Rivero Fernández, Miguel; Vázquez Romero, Manuel; Angueira Lapeña, Teresa; Arranz de la Mata, Gemma; Boixeda de Miquel, Daniel

    2008-12-01

    Metformin is an oral antidiabetic agent frequently used to manage type II diabetes. This drug produces nonspecific gastrointestinal symptoms in 5-20% of patients and, more rarely, has also been associated with severe adverse effects such as lactic acidosis. Only a few isolated cases of hepatotoxicity due to this drug have been documented. We report the case of an 83-year-old man with constitutional syndrome and hepatic biochemical alterations, which were attributed to metformin after ruling out an oncologic etiology and observing complete clinical and biochemical resolution after withdrawal of the drug.

  4. Possible hepatotoxicity of chronic marijuana usage

    OpenAIRE

    Borini, Paulo; Guimarães, Romeu Cardoso; Borini, Sabrina Bicalho

    2004-01-01

    CONTEXT: Hepatotoxicity is a potential complication from the usage of various illicit drugs, possibly consequent to their liver metabolism, but information on this is scarce in the medical literature. OBJECTIVE: To study the occurrence of clinical and laboratory hepatic alterations in chronic marijuana users, from the use of marijuana on its own or in association with other legal or illicit drugs. TYPE OF STUDY: transversal study SETTING: Hospital Espírita de Marília, Marília, São Paulo, Braz...

  5. Hydroxycut hepatotoxicity: A case series and review of liver toxicity from herbal weight loss supplements

    Institute of Scientific and Technical Information of China (English)

    Lily Dare; Jennifer Hewett; Joseph Kartaik Lim

    2008-01-01

    Dietary supplements represent an increasingly common source of drug-induced liver injury. Hydroxycut is a popular weight loss supplement which has previously been linked to hepatotoxiciLy, although the individual chemical components underlying liver injury remain poorly understood. We report two cases of acute hepatitis in the seLLing of Hydroxycut exposure and describe possible mechanisms of liver injury. We also comprehensively review and summarize the existing literature on commonly used weight loss supplements,and their individual components which have demonstrated potential for liver toxicity. An increased effort to screen for and educate patients and physicians about supplement-associated hepatotoxicity is warranted.

  6. Hepatotoxicity of illegal home-made alcohols.

    Science.gov (United States)

    Gökce, Hasan; Akcan, Ramazan; Celikel, Adnan; Zeren, Cem; Ortanca, Ibrahim; Demirkiran, Sumeyra

    2016-10-01

    Alcohol-related hepatotoxicity is not only caused by excessive alcohol consumption but also caused and even accelerated by hepatotoxic ingredients other than ethanol. Concentrations of hepatotoxic substances might be significantly high, particularly in illegally produced home-made alcohols. In this study we aim to analyze the hepatotoxic effects of a home-made alcohol traditionally called "bogma raki" in Turkey. Fifty Wistar albino male rats were used. Five groups were randomly formed with ten animals in each. Besides laboratory diets, groups were fed as follows: Group 1 (control group) distilled water; Group 2 bogma raki with distilled water (%44 (v/v), 9.2 ml/kg/day); Group 3 bogma raki with distilled water (%44 (v/v), 9.2 ml/kg/day)+walnut (10 g/kg/day); Group 4 whisky with distilled water (%40 (v/v), 9.2 ml/kg/day); Group 5 distilled water + walnut (10 g/kg/day), for 28 days. The toxicological analysis of The spirits were analyzed using Hewlett-Packard (Palo Alto, CA) GC/MS system with HP 6890 gas chromatograph, an HP 5972 mass selective detector (MSD) and an HP 6890 automatic liquid sampler GC/MS; the pressure of the carrier gas helium was 6.0 bar and the split value with a ratio of 1:100. The injection unit temperature set to 250 °C and MS quadrupole temperature set to 280 °C. The MS quadrupole detector ionization energy set to 70 eV. The initial column temperature was 60 °C (for 4 min) programmed by 6 °C/min to final temperature 160 °C and kept for 8 min at 160 °C. Utilized whisky and bogma raki samples were analyzed for the amounts of trans-anethole, ethanol, methanol, 1-propanolol, butanol, 2-butanol, 2-methyl-1-propanolol (isobutanol) and 3-methylbutanol (isoamyl alcohol). Histopathological changes in liver tissues were graded as follows; normal = 0 (illegally produced raki sample (%v/v) was as follows: trans-anethole %1.93, ethanol %95.70, 2-methyl-1-propanolol (isobutanol) %0.19, asetic acid %0.25, 3-methylbutanol (isoamyl

  7. Mechanisms of circadian rhythmicity of carbon tetrachloride hepatotoxicity.

    Science.gov (United States)

    Bruckner, James V; Ramanathan, Raghupathy; Lee, K Monica; Muralidhara, Srinivasa

    2002-01-01

    The toxicity of carbon tetrachloride (CCl(4)) and certain other chemicals varies over a 24-h period. Because the metabolism of some drugs follows a diurnal rhythm, it was decided to investigate whether the hepatic metabolic activation of CCl(4) was rhythmic and coincided in time with maximum susceptibility to CCl(4) hepatotoxicity. A related objective was to test the hypothesis that abstinence from food during the sleep cycle results in lipolysis and formation of acetone, which participates in induction of liver microsomal cytochrome P450IIE1 (CYP2E1), resulting in a diurnal increase in CCl(4) metabolic activation and acute liver injury. Groups of fed and fasted male Sprague-Dawley rats were given a single oral dose of 800 mg of CCl(4)/kg at 2- to 4-h intervals over a 24-h period. Serum enzyme activities, measured 24 h post dosing as indices of acute liver injury, exhibited distinct maxima in both fed and fasted animals dosed with CCl(4) near the beginning of their dark/active cycle. Blood acetone, hepatic CYP2E1 activity, and covalent binding of (14)CCl(4)/metabolites to hepatic microsomal proteins in untreated rats fed ad libitum followed circadian rhythms similar to that of susceptibility to CCl(4). Parallel fluctuations of greater amplitude were seen in rats fasted for 24 h. Hepatic glutathione levels were lowest at the time of greatest susceptibility to CCl(4). Acetone dose-response experiments showed high correlations between blood acetone levels, CYP2E1 induction, and CCl(4)-induced liver injury. Pretreatment with diallyl sulfide suppressed CYP2E1 and abolished the circadian rhythmicity of susceptibility to CCl(4). These findings provide additional support for acetone's physiological role in CYP2E1 induction and for CYP2E1's role in modulating CCl(4) chronotoxicity in rats.

  8. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

    International Nuclear Information System (INIS)

    Henninger, Christian; Huelsenbeck, Johannes; Huelsenbeck, Stefanie; Grösch, Sabine; Schad, Arno; Lackner, Karl J.; Kaina, Bernd; Fritz, Gerhard

    2012-01-01

    Liver is the main detoxifying organ and therefore the target of high concentrations of genotoxic compounds, such as environmental carcinogens and anticancer drugs. Here, we investigated the usefulness of lovastatin, which is nowadays widely used for lipid lowering purpose, as a hepatoprotective drug following the administration of the anthracycline derivative doxorubicin in vivo. To this end, BALB/c mice were exposed to either a single high dose or three consecutive low doses of doxorubicin. Acute and subacute hepatotoxicities were analyzed with or without lovastatin co-treatment. Lovastatin protected the liver against doxorubicin-induced acute pro-inflammatory and pro-fibrotic stress responses as indicated by an attenuated mRNA expression of tumor necrosis factor alpha (TNFα) and connective tissue growth factor (CTGF), respectively. Hepatoprotection by lovastatin was due to a reduced induction of DNA damage following doxorubicin treatment. The statin also mitigated subacute anthracycline-provoked hepatotoxicity as shown on the level of doxorubicin- and epirubicin-stimulated CTGF mRNA expression as well as histopathologically detectable fibrosis and serum concentration of marker enzymes of hepatotoxicity (GPT/GLDH). Kidney damage following doxorubicin exposure was not detectable under our experimental conditions. Moreover, lovastatin showed multiple inhibitory effects on doxorubicin-triggered hepatic expression of genes involved in oxidative stress response, drug transport, DNA repair, cell cycle progression and cell death. Doxorubicin also stimulated the formation of ceramides. Ceramide production, however, was not blocked by lovastatin, indicating that hepatoprotection by lovastatin is independent of the sphingolipid metabolism. Overall, the data show that lovastatin is hepatoprotective following genotoxic stress induced by anthracyclines. Based on the data, we hypothesize that statins might be suitable to lower hepatic injury following anthracycline

  9. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Henninger, Christian [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf (Germany); Huelsenbeck, Johannes; Huelsenbeck, Stefanie [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Grösch, Sabine [Institute of Clinical Pharmacology, Johann Wolfgang Goethe University Frankfurt, Theodor Stern Kai 7, D-60590 Frankfurt/Main (Germany); Schad, Arno [Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Lackner, Karl J. [Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Kaina, Bernd [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Fritz, Gerhard, E-mail: fritz@uni-duesseldorf.de [Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz (Germany); Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf (Germany)

    2012-05-15

    Liver is the main detoxifying organ and therefore the target of high concentrations of genotoxic compounds, such as environmental carcinogens and anticancer drugs. Here, we investigated the usefulness of lovastatin, which is nowadays widely used for lipid lowering purpose, as a hepatoprotective drug following the administration of the anthracycline derivative doxorubicin in vivo. To this end, BALB/c mice were exposed to either a single high dose or three consecutive low doses of doxorubicin. Acute and subacute hepatotoxicities were analyzed with or without lovastatin co-treatment. Lovastatin protected the liver against doxorubicin-induced acute pro-inflammatory and pro-fibrotic stress responses as indicated by an attenuated mRNA expression of tumor necrosis factor alpha (TNFα) and connective tissue growth factor (CTGF), respectively. Hepatoprotection by lovastatin was due to a reduced induction of DNA damage following doxorubicin treatment. The statin also mitigated subacute anthracycline-provoked hepatotoxicity as shown on the level of doxorubicin- and epirubicin-stimulated CTGF mRNA expression as well as histopathologically detectable fibrosis and serum concentration of marker enzymes of hepatotoxicity (GPT/GLDH). Kidney damage following doxorubicin exposure was not detectable under our experimental conditions. Moreover, lovastatin showed multiple inhibitory effects on doxorubicin-triggered hepatic expression of genes involved in oxidative stress response, drug transport, DNA repair, cell cycle progression and cell death. Doxorubicin also stimulated the formation of ceramides. Ceramide production, however, was not blocked by lovastatin, indicating that hepatoprotection by lovastatin is independent of the sphingolipid metabolism. Overall, the data show that lovastatin is hepatoprotective following genotoxic stress induced by anthracyclines. Based on the data, we hypothesize that statins might be suitable to lower hepatic injury following anthracycline

  10. Possible hepatotoxicity of chronic marijuana usage

    Directory of Open Access Journals (Sweden)

    Paulo Borini

    Full Text Available CONTEXT: Hepatotoxicity is a potential complication from the usage of various illicit drugs, possibly consequent to their liver metabolism, but information on this is scarce in the medical literature. OBJECTIVE: To study the occurrence of clinical and laboratory hepatic alterations in chronic marijuana users, from the use of marijuana on its own or in association with other legal or illicit drugs. TYPE OF STUDY: transversal study SETTING: Hospital Espírita de Marília, Marília, São Paulo, Brazil PARTICIPANTS: The study was made among 123 patients interned in the Hospital Espírita de Marília from October 1996 to December 1998, divided into 3 groups: 26 (21% using only marijuana, 83 (67.5% using marijuana and crack, and 14 (11.4% consuming marijuana and alcohol. PROCEDURES AND MAIN MEASUREMENTS: Patients were examined clinically with special emphasis on types of drugs used, drug intake route, age when consumption began, length and pattern of usage, presence of tattooing, jaundice, hepatomegaly and splenomegaly. Serum determinations of total proteins, albumin, globulin, total and fractions of bilirubin, aspartate (AST and alanine (ALT aminotransferases, alkaline phosphatase (AP, gamma-glutamyltransferase and prothrombin activity were performed. RESULTS: Among users of only marijuana, hepatomegaly was observed in 57.7% and splenomegaly in 73.1%, and slightly elevated AST (42.3%, ALT (34.6% and AP (53.8%. The three groups did not differ significantly in the prevalence of hepatomegaly, splenomegaly and hepatosplenomegaly. The group using both marijuana and alcohol showed the highest prevalence of alterations and highest levels of aminotransferases. Mean AP levels were above normal in all groups. CONCLUSIONS: Chronic marijuana usage, on its own or in association with other drugs, was associated with hepatic morphologic and enzymatic alterations. This indicates that cannabinoids are possible hepatotoxic substances.

  11. Modulation of O-GlcNAc Levels in the Liver Impacts Acetaminophen-Induced Liver Injury by Affecting Protein Adduct Formation and Glutathione Synthesis.

    Science.gov (United States)

    McGreal, Steven R; Bhushan, Bharat; Walesky, Chad; McGill, Mitchell R; Lebofsky, Margitta; Kandel, Sylvie E; Winefield, Robert D; Jaeschke, Hartmut; Zachara, Natasha E; Zhang, Zhen; Tan, Ee Phie; Slawson, Chad; Apte, Udayan

    2018-04-01

    Overdose of acetaminophen (APAP) results in acute liver failure. We have investigated the role of a posttranslational modification of proteins called O-GlcNAcylation, where the O-GlcNAc transferase (OGT) adds and O-GlcNAcase (OGA) removes a single β-D-N-acetylglucosamine (O-GlcNAc) moiety, in the pathogenesis of APAP-induced liver injury. Hepatocyte-specific OGT knockout mice (OGT KO), which have reduced O-GlcNAcylation, and wild-type (WT) controls were treated with 300 mg/kg APAP and the development of injury was studied over a time course from 0 to 24 h. OGT KO mice developed significantly lower liver injury as compared with WT mice. Hepatic CYP2E1 activity and glutathione (GSH) depletion following APAP treatment were not different between WT and OGT KO mice. However, replenishment of GSH and induction of GSH biosynthesis genes were significantly faster in the OGT KO mice. Next, male C57BL/6 J mice were treated Thiamet-G (TMG), a specific inhibitor of OGA to induce O-GlcNAcylation, 1.5 h after APAP administration and the development of liver injury was studied over a time course of 0-24 h. TMG-treated mice exhibited significantly higher APAP-induced liver injury. Treatment with TMG did not affect hepatic CYP2E1 levels, GSH depletion, APAP-protein adducts, and APAP-induced mitochondrial damage. However, GSH replenishment and GSH biosynthesis genes were lower in TMG-treated mice after APAP overdose. Taken together, these data indicate that induction in cellular O-GlcNAcylation exacerbates APAP-induced liver injury via dysregulation of hepatic GSH replenishment response.

  12. Sub-acute hepatotoxicity of Pausinystalia yohimbe bark extract ...

    African Journals Online (AJOL)

    Corynanthe yohibi) (Family, Rubiaceae) is a true aphrodisiac used as a possible treatment for organic, psychogenic and substance induced erectile impotence and other male sexual dysfunctions. It increases blood flow to erectile tissues and exerts its ...

  13. Protective effect of agmatine in acute chlorpromazine hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Bratislav Dejanovic

    2014-01-01

    Full Text Available The present study focused on potentially beneficial effects of agmatine on oxidative stress development in the liver during chlorpromazine treatment in rats. We wanted to examine the role of reactive oxygen species and efficiency of antioxidant protection through the determination of malondylaldehyde and total glutathione concentrations in rat liver homogenate, as well as plasma concentrations of malonylaldehyde and sulfhydryl groups after the treatment. Also, liver tissue sections were examined to follow histological changes. Chlorpromazine was applied intraperitoneally at a single dose of 38.7 mg/kg b.w. The second group was treated with both chlorpromazine (at a single dose of 38.7 mg/kg b.w. and agmatine (at a single dose of 75 mg/kg b.w.. Agmatine was applied immediately after the chlorpromazine. The control group was treated with 0.9% saline solution in the same manner. Rats were sacrificed by decapitation 24 h after the treatment and biochemical and immunohistochemical examinations were performed. Analysis of data showed that treatment with agmatine significantly attenuated the oxidative stress indicators as evidenced by lowering malonylaldehyde concentrations in the liver and in plasma while not affecting liver concentrations of total glutathione and plasma concentration of sulfhydryl groups. Additionally, histological evaluation revealed the improvement of liver damage in this respect. The presented data indicated that intraperitoneally administered agmatine protects against chlorpromazine-induced liver disease in rats.

  14. Amelioration of lead-induced hepatotoxicity by Allium sativum ...

    African Journals Online (AJOL)

    2010-01-07

    Jan 7, 2010 ... The efficacy of garlic (Allium sativum) to reduce hepatotoxicity induced by ..... fatty acids having double bonds, largely present in the phospholipids of .... disulfide, and diallyl disulfide, possess antioxidant prop- erties and can ...

  15. Hepatotoxic and Nephrotoxic Effects of Petroleum Fumes on Petrol ...

    African Journals Online (AJOL)

    DR SULEIMAN

    Hepatotoxic and Nephrotoxic Effects of Petroleum Fumes on Petrol Attendants in Ibadan, Nigeria. *1A.L. Ogunneye ... inhalation of petrol fumes is associated with adverse effect on the kidney and liver function. ..... neurotoxicity in mice. African ...

  16. Herbal hepatotoxicity: a tabular compilation of reported cases.

    Science.gov (United States)

    Teschke, Rolf; Wolff, Albrecht; Frenzel, Christian; Schulze, Johannes; Eickhoff, Axel

    2012-11-01

    Herbal hepatotoxicity is a field that has rapidly grown over the last few years along with increased use of herbal products worldwide. To summarize the various facets of this disease, we undertook a literature search for herbs, herbal drugs and herbal supplements with reported cases of herbal hepatotoxicity. A selective literature search was performed to identify published case reports, spontaneous case reports, case series and review articles regarding herbal hepatotoxicity. A total of 185 publications were identified and the results compiled. They show 60 different herbs, herbal drugs and herbal supplements with reported potential hepatotoxicity, additional information including synonyms of individual herbs, botanical names and cross references are provided. If known, details are presented for specific ingredients and chemicals in herbal products, and for references with authors that can be matched to each herbal product and to its effect on the liver. Based on stringent causality assessment methods and/or positive re-exposure tests, causality was highly probable or probable for Ayurvedic herbs, Chaparral, Chinese herbal mixture, Germander, Greater Celandine, green tea, few Herbalife products, Jin Bu Huan, Kava, Ma Huang, Mistletoe, Senna, Syo Saiko To and Venencapsan(®). In many other publications, however, causality was not properly evaluated by a liver-specific and for hepatotoxicity-validated causality assessment method such as the scale of CIOMS (Council for International Organizations of Medical Sciences). This compilation presents details of herbal hepatotoxicity, assisting thereby clinical assessment of involved physicians in the future. © 2012 John Wiley & Sons A/S.

  17. Metabolism by conjugation appears to confer resistance to paracetamol (acetaminophen) hepatotoxicity in the cynomolgus monkey.

    Science.gov (United States)

    Yu, Hong; Barrass, Nigel; Gales, Sonya; Lenz, Eva; Parry, Tony; Powell, Helen; Thurman, Dale; Hutchison, Michael; Wilson, Ian D; Bi, Luke; Qiao, Junwen; Qin, Qiuping; Ren, Jin

    2015-03-01

    1. Paracetamol overdose remains the leading cause of acute liver failure in humans. This study was undertaken in cynomolgus monkeys to study the pharmacokinetics, metabolism and the potential for hepatotoxic insult from paracetamol administration as a possible model for human toxicity. 2. No adverse effects were observed for doses of up to 900 mg/kg/d for 14 d. Only minor sporadic increases in alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase in a number of animals were observed, with no clear dose response. 3. Toxicokinetic analysis showed good plasma exposure, albeit with less than proportional rises in Cmax and AUC, with increasing dose. The Cmax values in monkey were up to 3.5 times those associated with human liver toxicity and the AUC approx. 1000 times those associated with liver enzyme changes in 31-44% of human subjects. 4. Metabolite profiling of urine by (1)H NMR spectroscopy revealed paracetamol and its glucuronide and sulphate metabolites. Glutathione-derived metabolites, e.g. the cysteinyl conjugate, were only present in very low concentrations whilst the mercapturate was not detected. 5. These in vivo observations demonstrated that the cynomolgus monkey is remarkably resistant to paracetamol-induced toxicity and a poor model for investigating paracetamol-related hepatotoxicity in humans.

  18. Pregnane X Receptor-Humanized Mice Recapitulate Gender Differences in Ethanol Metabolism but Not Hepatotoxicity.

    Science.gov (United States)

    Spruiell, Krisstonia; Gyamfi, Afua A; Yeyeodu, Susan T; Richardson, Ricardo M; Gonzalez, Frank J; Gyamfi, Maxwell A

    2015-09-01

    Both human and rodent females are more susceptible to developing alcoholic liver disease following chronic ethanol (EtOH) ingestion. However, little is known about the relative effects of acute EtOH exposure on hepatotoxicity in female versus male mice. The nuclear receptor pregnane X receptor (PXR; NR1I2) is a broad-specificity sensor with species-specific responses to toxic agents. To examine the effects of the human PXR on acute EtOH toxicity, the responses of male and female PXR-humanized (hPXR) transgenic mice administered oral binge EtOH (4.5 g/kg) were analyzed. Basal differences were observed between hPXR males and females in which females expressed higher levels of two principal enzymes responsible for EtOH metabolism, alcohol dehydrogenase 1 and aldehyde dehydrogenase 2, and two key mediators of hepatocyte replication and repair, cyclin D1 and proliferating cell nuclear antigen. EtOH ingestion upregulated hepatic estrogen receptor α, cyclin D1, and CYP2E1 in both genders, but differentially altered lipid and EtOH metabolism. Consistent with higher basal levels of EtOH-metabolizing enzymes, blood EtOH was more rapidly cleared in hPXR females. These factors combined to provide greater protection against EtOH-induced liver injury in female hPXR mice, as revealed by markers for liver damage, lipid peroxidation, and endoplasmic reticulum stress. These results indicate that female hPXR mice are less susceptible to acute binge EtOH-induced hepatotoxicity than their male counterparts, due at least in part to the relative suppression of cellular stress and enhanced expression of enzymes involved in both EtOH metabolism and hepatocyte proliferation and repair in hPXR females. U.S. Government work not protected by U.S. copyright.

  19. Acute Liver Toxicity due to Efavirenz/Emtricitabine/Tenofovir

    Directory of Open Access Journals (Sweden)

    Rashmee Patil

    2015-01-01

    Full Text Available The fixed-dose combination of Efavirenz/Emtricitabine/Tenofovir is a first-line agent for the treatment of HIV; however few cases have reported hepatotoxicity associated with the drug. We report a case of Efavirenz/Emtricitabine/Tenofovir-associated hepatotoxicity presenting mainly with hepatocellular injury characterized by extremely elevated aminotransferase levels, which resolved without acute liver failure or need for liver transplant referral.

  20. Hepatotoxic constituents and toxicological mechanism of Xanthium strumarium L. fruits.

    Science.gov (United States)

    Xue, Li-Ming; Zhang, Qiao-Yan; Han, Ping; Jiang, Yi-Ping; Yan, Rong-Di; Wang, Yang; Rahman, Khalid; Jia, Min; Han, Ting; Qin, Lu-Ping

    2014-03-14

    In the recent years, the international community has attached increasing importance to possible toxicity associated with Traditional Chinese Medicine (TCM). And hepatotoxicity is one of the major concerns, a fundamental pathological process induced by toxicant. This paper is in an attempt to identify the hepatotoxic components in Xanthium strumarium L. fruits (XSF) and interpret the toxicological mechanism induced by XSF. XSF extract was prepared and seven characteristic components were isolated and identified in XSF water extracts. We evaluated their hepatotoxicity effect on cell proliferation and lactate dehydrogenase (LDH) activity in L-02 and BRL liver cell line. An integrated metabonomics study using high-resolution (1)H nuclear magnetic resonance ((1)H NMR) spectroscopy combined with multivariate statistical analysis was undertake to elucidate the hepatotoxicity mechanism induced in rats by XSF. The urine and serum metabolites were measured after treatment of rats with XSF (7.5, 15.0 and 30.0 g/kg/day) for 5 days. The results showed that atractyloside, carboxyatractyloside, 4'-desulphate-atractyloside and XSF induced significant cytotoxic effects in both L-02 and BRL liver cell lines, indicating that atractyloside, carboxyatractyloside, and 4'-desulphate-atractyloside were the toxic components of XSF. When rats were treated with XSF at 30.0 g/kg the hepatotoxicity was reflected in the changes observed in serum biochemical profiles and by the histopathological examination of the liver. The levels of VLDL/LDL, 3-HB, lactate, acetate, acetone and glutamate in serum were increased in this group, while d-glucose, choline and valine were decreased. The elevation in the levels of succinate, citrate, 2-oxo-glutamate, glycine, 3-HB, acetate, lactate, hippurate, dimethylglycine, methylamine, dimethylamine, phenylalanine and tryptophan was observed in urine, in contrast a reduction in the intensities of taurine, d-glucose, N-acetyl-glucoprotein and trimethylamine

  1. Hepatotoxicity after liver irradiation in children and adolescents. Results from the RiSK

    Energy Technology Data Exchange (ETDEWEB)

    Roesler, Pascal; Christiansen, Hans [Medical School Hannover, Department of Radiotherapy and Special Oncology, Hannover (Germany); Kortmann, Rolf-Dieter [University of Leipzig, Department of Radiotherapy, Leipzig (Germany); Martini, Carmen [University Hospital of Freiburg, Department of Radiotherapy, Freiburg im Breisgau (Germany); Matuschek, Christiane [Heinrich-Heine University of Duesseldorf, Department of Radiotherapy, Medical Faculty, Duesseldorf (Germany); Meyer, Frank [Hospital Augsburg, Department of Radiotherapy, Augsburg (Germany); Ruebe, Christian [University Hospital of Homburg/Saar, Department of Radiotherapy, Homburg/Saar (Germany); Langer, Thorsten [University Hospital of Schleswig-Holstein, Department of Pediatrics, Pediatric Oncology, Campus Luebeck (Germany); Koch, Raphael [University of Muenster, Institute of Biostatistics and Clinical Research, Muenster (Germany); Eich, Hans Theodor; Willich, Normann [University Hospital of Muenster, Department of Radiotherapy, Muenster (Germany); Steinmann, Diana [Medical School Hannover, Department of Radiotherapy and Special Oncology, Hannover (Germany); University Hospital of Muenster, Department of Radiotherapy, Muenster (Germany)

    2015-05-01

    The aim of this study was to evaluate acute and late radiotherapy-associated hepatotoxicity in consideration of dose-volume effects and liver function in childhood and adolescence. Since 2001, irradiated children and adolescents in Germany have been prospectively documented in the ''Register of Treatment-Associated Late Effects After Radiotherapy of Malignant Diseases in Childhood and Adolescence (RiSK)'' using standardized forms. Toxicity was graded according to the Radiation Therapy Oncology Group (RTOG) criteria. Until April 2012, 1,392 children and adolescents from 62 radiotherapy centers were recruited. In all, 216 patients underwent irradiation of the liver (median age 9 years, range 1-18 years, 70 patients with total-body irradiation, TBI). For 75 % of patients without TBI, information on acute toxicity of the liver was available: 24 patients had acute toxicity of grade 1-4 (grade 1, 2, and 4, in 20, 3, and 1 patient, respectively), including five patients receiving simultaneous hepatotoxic chemotherapy. Information on late toxicity was documented in 465 forms from 216 patients, with a median follow-up of 2 years. A maximum grade of toxicity of ≥ 0 occurred in 18 patients over time (with grade 1, 2, and 3 toxicity occurring in 15, 2, and 1 patient, respectively), including three patients (17 %) with TBI. One of them received simultaneous hepatotoxic chemotherapy. In multivariable analysis, volume-dose correlations showed no statistically noticeable effect on acute or chronic toxicity. Only low hepatotoxicity developed in children after irradiation of various abdominal and thoracic tumors. Due to the low radiation doses to the liver (median liver dose = 5 Gy) and the low toxicities that were consecutively observed, dose-volume curves for liver toxicity could not be established. These findings reflect the cautious attitude of radiation oncologists in terms of attributable liver doses in the treatment of the investigated tumor entities. It

  2. Quercitrin from Toona sinensis (Juss. M.Roem. Attenuates Acetaminophen-Induced Acute Liver Toxicity in HepG2 Cells and Mice through Induction of Antioxidant Machinery and Inhibition of Inflammation

    Directory of Open Access Journals (Sweden)

    Van-Long Truong

    2016-07-01

    Full Text Available Quercitrin is found in many kinds of vegetables and fruits, and possesses various bioactive properties. The aim of the present study was to elucidate hepatoprotective mechanisms of quercitrin isolated from Toona sinensis (Juss. M.Roem. (syn. Cedrela sinensis Juss., using acetaminophen (APAP-treated HepG2 cell and animal models. In an in vitro study, quercitrin suppressed the production of reactive oxygen species and enhanced expression of nuclear factor E2-related factor 2 (Nrf2, activity of antioxidant response element (ARE-reporter gene, and protein levels of NADPH: quinone oxidoreductase 1 (NQO1, catalase (CAT, glutathione peroxidase (GPx, and superoxide dismutase 2 (SOD-2 in APAP-treated HepG2 cells. In an in vivo study, Balb/c mice were orally administered with 10 or 50 mg/kg of quercitrin for 7 days and followed by the injection with single dose of 300 mg/kg APAP. Quercitrin decreased APAP-caused elevation of alanine aminotransferase and aspartate aminotransferase levels, liver necrosis, the expression of pro-inflammatory factors including inducible nitric oxide synthase, cyclooxygenase 2 and inerleukin-1β, and phosphorylation of kinases including c-Jun N-terminal kinase and p38. Quercitrin restored protein levels of Nrf2, NQO1 and activities and expressions of CAT, GPx, SOD-2. The results suggested that quercitrin attenuates APAP-induced liver damage by the activation of defensive genes and the inhibition of pro-inflammatory genes via the suppressions of JNK and p38 signaling.

  3. Activation of Nrf2 protects against triptolide-induced hepatotoxicity.

    Directory of Open Access Journals (Sweden)

    Jia Li

    Full Text Available Triptolide, the major active component of Tripterygium wilfordii Hook f. (TWHF, has a wide range of pharmacological activities. However, the toxicities of triptolide, particularly the hepatotoxicity, limit its clinical application. The hepatotoxicity of triptolide has not been well characterized yet. The aim of this study was to investigate the role of NF-E2-related factor 2 (Nrf2 in triptolide-induced toxicity and whether activation of Nrf2 could protect against triptolide-induced hepatotoxicity. The results showed that triptolide caused oxidative stress and cell damage in HepG2 cells, and these toxic effects could be aggravated by Nrf2 knockdown or be counteracted by overexpression of Nrf2. Treatment with a typical Nrf2 agonist, sulforaphane (SFN, attenuated triptolide-induced liver dysfunction, structural damage, glutathione depletion and decrease in antioxidant enzymes in BALB/C mice. Moreover, the hepatoprotective effect of SFN on triptolide-induced liver injury was associated with the activation of Nrf2 and its downstream targets. Collectively, these results indicate that Nrf2 activation protects against triptolide-induced hepatotoxicity.

  4. Influence of extraction methods on the hepatotoxicity of Azadirachta ...

    African Journals Online (AJOL)

    The influence of extraction methods: Cold aqueous (CA) hot aqueous (HA) and alcoholic extraction (AE) methods on the hepatotoxic effect of Azadirachta indica bark extract (ABC) was investigated using albino rats. A total of forty eight rats were divided into three groups of sixteen rats equally for the extraction methods.

  5. The Effects of Bitter Kola Supplemented Diet on Hepatotoxicity of ...

    African Journals Online (AJOL)

    MICHAEL

    supplemented rat chow and mercury contaminated water, group V animals were ... hepatotoxic effects of the heavy metal indirectly assessed by measurement of the serum levels of alkaline .... III vs V: Group IV vs V.P-values less than 0.05.

  6. Comparative Hepatotoxicity Test of Cadmium and Lead in Rats ...

    African Journals Online (AJOL)

    Background: Adverse environmental impacts include contamination of water, soil, and phytotoxicity from excessive heavy metals dispersed from mines and smelter sites leading to potential risk to human health. This study investigated the comparative hepatotoxicity test of mining pond waters used for domestic purposes in ...

  7. Hepatotoxic and Nephrotoxic Effects of Petroleum Fumes on Petrol ...

    African Journals Online (AJOL)

    The present study was conducted to evaluate the hepatotoxic and nephrotoxic effects of petroleum fumes on male and female petrol attendants. Investigations had been carried out on thirty (30) adult petrol attendants from different filling stations in Ibadan metropolis of Nigeria with ten (10) healthy adults as control. All the ...

  8. Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism

    Directory of Open Access Journals (Sweden)

    Xinmiao Yan

    2016-03-01

    Full Text Available Pyrrolizidine Alkaloids (PAs are currently one of the most important botanical hepatotoxic ingredients. Glutathion (GSH metabolism is the most reported pathway involved in hepatotoxicity mechanism of PAs. We speculate that, for different PAs, there should be a common mechanism underlying their hepatotoxicity in GSH metabolism. Computational methods were adopted to test our hypothesis in consideration of the limitations of current experimental approaches. Firstly, the potential targets of 22 PAs (from three major PA types in GSH metabolism were identified by reverse docking; Secondly, glutathione S-transferase A1 (GSTA1 and glutathione peroxidase 1 (GPX1 targets pattern was found to be a special characteristic of toxic PAs with stepwise multiple linear regressions; Furthermore, the molecular mechanism underlying the interactions within toxic PAs and these two targets was demonstrated with the ligand-protein interaction analysis; Finally, GSTA1 and GPX1 were proved to be significant nodes in GSH metabolism. Overall, toxic PAs could be identified by GSTA1 and GPX1 targets pattern, which suggests their common hepatotoxicity mechanism: the interfering of detoxication in GSH metabolism. In addition, all the strategies developed here could be extended to studies on toxicity mechanism of other toxins.

  9. Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism.

    Science.gov (United States)

    Yan, Xinmiao; Kang, Hong; Feng, Jun; Yang, Yiyan; Tang, Kailin; Zhu, Ruixin; Yang, Li; Wang, Zhengtao; Cao, Zhiwei

    2016-03-07

    Pyrrolizidine Alkaloids (PAs) are currently one of the most important botanical hepatotoxic ingredients. Glutathion (GSH) metabolism is the most reported pathway involved in hepatotoxicity mechanism of PAs. We speculate that, for different PAs, there should be a common mechanism underlying their hepatotoxicity in GSH metabolism. Computational methods were adopted to test our hypothesis in consideration of the limitations of current experimental approaches. Firstly, the potential targets of 22 PAs (from three major PA types) in GSH metabolism were identified by reverse docking; Secondly, glutathione S-transferase A1 (GSTA1) and glutathione peroxidase 1 (GPX1) targets pattern was found to be a special characteristic of toxic PAs with stepwise multiple linear regressions; Furthermore, the molecular mechanism underlying the interactions within toxic PAs and these two targets was demonstrated with the ligand-protein interaction analysis; Finally, GSTA1 and GPX1 were proved to be significant nodes in GSH metabolism. Overall, toxic PAs could be identified by GSTA1 and GPX1 targets pattern, which suggests their common hepatotoxicity mechanism: the interfering of detoxication in GSH metabolism. In addition, all the strategies developed here could be extended to studies on toxicity mechanism of other toxins.

  10. Hepatotoxicity associated with the dietary supplement OxyELITE Pro™ — Hawaii, 2013

    Science.gov (United States)

    Johnston, David I.; Chang, Arthur; Viray, Melissa; Chatham-Stephens, Kevin; He, Hua; Taylor, Ethel; Wong, Linda L.; Schier, Joshua; Martin, Colleen; Fabricant, Daniel; Salter, Monique; Lewis, Lauren; Park, Sarah Y.

    2015-01-01

    Dietary supplements are increasingly marketed to and consumed by the American public for a variety of purported health benefits. On 9 September 2013, the Hawaii Department of Health (HDOH) was notified of a cluster of acute hepatitis and fulminant hepatic failure among individuals with exposure to the dietary supplement OxyELITE Pro™ (OEP). HDOH conducted an outbreak investigation in collaboration with federal partners. Physicians were asked to report cases, defined as individuals with acute onset hepatitis of unknown etiology on or after 1 April 2013, a history of weight-loss/muscle-building dietary supplement use during the 60 days before illness onset, and residence in Hawaii during the period of exposure. Reported cases’ medical records were reviewed, questionnaires were administered, and a product investigation, including chemical analyses and trace back, was conducted. Of 76 reports, 44 (58%) met case definition; of these, 36 (82%) reported OEP exposure during the two months before illness. No other common supplements or exposures were observed. Within the OEP-exposed subset, two patients required liver transplantation, and a third patient died. Excessive product dosing was not reported. No unique lot numbers were identified; there were multiple mainland distribution points, and lot numbers common to cases in Hawaii were also identified in continental states. Product analysis found consumed products were consistent with labeled ingredients; the mechanism of hepatotoxicity was not identified. We report one of the largest statewide outbreaks of dietary supplement-associated hepatotoxicity. The implicated product was OEP. The increasing popularity of dietary supplements raises the potential for additional clusters of dietary supplement-related adverse events. PMID:26538199

  11. Hepatotoxicity associated with the dietary supplement OxyELITE Pro™ - Hawaii, 2013.

    Science.gov (United States)

    Johnston, David I; Chang, Arthur; Viray, Melissa; Chatham-Stephens, Kevin; He, Hua; Taylor, Ethel; Wong, Linda L; Schier, Joshua; Martin, Colleen; Fabricant, Daniel; Salter, Monique; Lewis, Lauren; Park, Sarah Y

    2016-01-01

    Dietary supplements are increasingly marketed to and consumed by the American public for a variety of purported health benefits. On 9 September 2013, the Hawaii Department of Health (HDOH) was notified of a cluster of acute hepatitis and fulminant hepatic failure among individuals with exposure to the dietary supplement OxyELITE Pro™ (OEP). HDOH conducted an outbreak investigation in collaboration with federal partners. Physicians were asked to report cases, defined as individuals with acute onset hepatitis of unknown etiology on or after 1 April 2013, a history of weight-loss/muscle-building dietary supplement use during the 60 days before illness onset, and residence in Hawaii during the period of exposure. Reported cases' medical records were reviewed, questionnaires were administered, and a product investigation, including chemical analyses and traceback, was conducted. Of 76 reports, 44 (58%) met case definition; of these, 36 (82%) reported OEP exposure during the two months before illness. No other common supplements or exposures were observed. Within the OEP-exposed subset, two patients required liver transplantation, and a third patient died. Excessive product dosing was not reported. No unique lot numbers were identified; there were multiple mainland distribution points, and lot numbers common to cases in Hawaii were also identified in continental states. Product analysis found consumed products were consistent with labeled ingredients; the mechanism of hepatotoxicity was not identified. We report one of the largest statewide outbreaks of dietary supplement-associated hepatotoxicity. The implicated product was OEP. The increasing popularity of dietary supplements raises the potential for additional clusters of dietary supplement-related adverse events. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  12. Hepatotoxicity of kaurene glycosides from Xanthium strumarium L. fruits in mice.

    Science.gov (United States)

    Wang, Yang; Han, Ting; Xue, Li-Ming; Han, Ping; Zhang, Qiao-Yan; Huang, Bao-Kang; Zhang, Hong; Ming, Qian-Liang; Peng, Wei; Qin, Lu-Ping

    2011-06-01

    The fruit of Xanthium strumarium L. (Cang-Er-Zi) is a traditional Chinese medicine that is used in curing nasal diseases and headache according to the Chinese Pharmacopoeia. However, clinical utilization of Xanthium strumarium is relatively limited because of its toxicity. The present investigation was carried out to evaluate the toxic effects on acute liver injury in mice of the two kaurene glycosides (atractyloside and carbxyatractyloside), which are main toxic constituents isolated from Fructus Xanthii on acute liver injury in mice. Histopathological examinations revealed that there were not obviously visible injury in lungs, heart, spleen, and the central nervous system in the mice by intraperitoneal injection of atractyloside (ATR, at the doses 50,125 and 200 mg/kg) and carbxyatractyloside (CATR, at the doses 50,100 and 150 mg/kg) for 5 days. However, it revealed extensive liver injuries compared with the normal group. In the determination of enzyme levels in serum, intraperitoneal injection of ATR and CATR resulted in significantly elevated serum alanine aminotransferase (ALT), asparate aminotransferase (AST), alkaline phosphatase (ALP) activities compared to controls. In the hepatic oxidative stress level, antioxidant-related enzyme activity assays showed that ATR and CATR administration significantly increased hepatic malondialdehyde (MDA) concentration, as well as decreased superoxide dismutase (SOD), catalase (CAT) activities and glutathione (GSH) concentration, and this was in good agreement with the results of serum aminotransferase activity and histopathological examinations. Taken together, our results demonstrate that kaurene glycosides induce hepatotoxicity in mice by way of its induction of oxidative stress as lipid peroxidation in liver, which merited further studies. Therefore, these toxic constituents explain, at least in part, the hepatotoxicity of X. strumarium L. in traditional medicine.

  13. Extracorporeal liver assist device to exchange albumin and remove endotoxin in acute liver failure: Results of a pivotal pre-clinical study.

    Science.gov (United States)

    Lee, Karla C L; Baker, Luisa A; Stanzani, Giacomo; Alibhai, Hatim; Chang, Yu Mei; Jimenez Palacios, Carolina; Leckie, Pamela J; Giordano, Paola; Priestnall, Simon L; Antoine, Daniel J; Jenkins, Rosalind E; Goldring, Christopher E; Park, B Kevin; Andreola, Fausto; Agarwal, Banwari; Mookerjee, Rajeshwar P; Davies, Nathan A; Jalan, Rajiv

    2015-09-01

    In acute liver failure, severity of liver injury and clinical progression of disease are in part consequent upon activation of the innate immune system. Endotoxaemia contributes to innate immune system activation and the detoxifying function of albumin, critical to recovery from liver injury, is irreversibly destroyed in acute liver failure. University College London-Liver Dialysis Device is a novel artificial extracorporeal liver assist device, which is used with albumin infusion, to achieve removal and replacement of dysfunctional albumin and reduction in endotoxaemia. We aimed to test the effect of this device on survival in a pig model of acetaminophen-induced acute liver failure. Pigs were randomised to three groups: Acetaminophen plus University College London-Liver Dialysis Device (n=9); Acetaminophen plus Control Device (n=7); and Control plus Control Device (n=4). Device treatment was initiated two h after onset of irreversible acute liver failure. The Liver Dialysis Device resulted in 67% reduced risk of death in acetaminophen-induced acute liver failure compared to Control Device (hazard ratio=0.33, p=0.0439). This was associated with 27% decrease in circulating irreversibly oxidised human non-mercaptalbumin-2 throughout treatment (p=0.046); 54% reduction in overall severity of endotoxaemia (p=0.024); delay in development of vasoplegia and acute lung injury; and delay in systemic activation of the TLR4 signalling pathway. Liver Dialysis Device-associated adverse clinical effects were not seen. The survival benefit and lack of adverse effects would support clinical trials of University College London-Liver Dialysis Device in acute liver failure patients. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  14. Xenobiotics-induced hepatotoxicity and an influence of HLA typisation

    Directory of Open Access Journals (Sweden)

    Žunić Miodrag

    2014-01-01

    Full Text Available Introduction: The increased reporting of cases of drug-induced liver injuries, reflects the growing number of new agents introduced into clinical practice in the last decades. It should be added to the modernization of industries, and new chemicals which it applied. Drug-induced liver injuries make up a persisting and challenging problem for physicians, health agencies and pharmaceutical firms. Research objectives: The aim of the study is the determination of the most common causes of drug-induced liver injury in our surroundings. We compared the importance of hepatotoxic action of drugs in relation to other noxa in human environment. We determinated the importance of the body sensitivity on the acting agents. We also examined the importance of different drugs in the development of hepatotoxicity, regardless the dose. Materials and methods: We analyzed 52 patients with a diagnosis of hepa-totoxic liver injury (medical history, detailed clinical evaluation of patients, histopathological analysis of the liver, abdominal ultra sound, laboratory determination of standard liver function tests and followed up for 12 months. In the period from 01.04. 2005 to 01.04.2009, in these patients of the Institute of Gastroenterology and Hepatology, Clinical Center of Serbia in Belgrade, we monitored liver functional tests and morphological findings. We used biological markers relevant for the differential diagnosis, monitoring of disease progression and response to therapy. The results of the patients with hepatotoxic liver injury were compared with the values of the findings of the 52 patients in the control group, with the diagnosis of chronic viral hepatitis, hospitalized in the same institution during the same time. Results: The causes of toxic liver damage in our study were following agents, classified into groups: Industrial toxins (8 patients, Food and beverages (9 pts, Antirheumatics and analgesics (6 pts, Antiarrhythmic drugs (4 pts Antilipemic (4 pts

  15. Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity

    Science.gov (United States)

    Antoine, Daniel James; Williams, Dominic P; Kipar, Anja; Laverty, Hugh; Park, B Kevin

    2010-01-01

    Acetaminophen (APAP) overdose is a major cause of acute liver failure and serves as a paradigm to elucidate mechanisms, predisposing factors and therapeutic interventions. The roles of apoptosis and inflammation during APAP hepatotoxicity remain controversial. We investigated whether fasting of mice for 24 h can inhibit APAP-induced caspase activation and apoptosis through the depletion of basal ATP. We also investigated in fasted mice the critical role played by inhibition of caspase-dependent cysteine 106 oxidation within high mobility group box-1 protein (HMGB1) released by ATP depletion in dying cells as a mechanism of immune activation. In fed mice treated with APAP, necrosis was the dominant form of hepatocyte death. However, apoptosis was also observed, indicated by K18 cleavage, DNA laddering and procaspase-3 processing. In fasted mice treated with APAP, only necrosis was observed. Inflammatory cell recruitment as a consequence of hepatocyte death was observed only in fasted mice treated with APAP or fed mice cotreated with a caspase inhibitor. Hepatic inflammation was also associated with loss in detection of serum oxidized-HMGB1. A significant role of HMGB1 in the induction of inflammation was confirmed with an HMGB1-neutralizing antibody. The differential response between fasted and fed mice was a consequence of a significant reduction in basal hepatic ATP, which prevented caspase processing, rather than glutathione depletion or altered APAP metabolism. Thus, the inhibition of caspase-driven apoptosis and HMGB1 oxidation by ATP depletion from fasting promotes an inflammatory response during drug-induced hepatotoxicity/liver pathology. PMID:20811657

  16. Chloroform ingestion causing severe gastrointestinal injury, hepatotoxicity and dermatitis confirmed with plasma chloroform concentrations.

    Science.gov (United States)

    Jayaweera, Dushan; Islam, Shawkat; Gunja, Naren; Cowie, Chris; Broska, James; Poojara, Latesh; Roberts, Michael S; Isbister, Geoffrey K

    2017-02-01

    Poisoning due to chloroform ingestion is rare. The classic features of acute chloroform toxicity include central nervous system (CNS) and respiratory depression, and delayed hepatotoxicity. A 30-year-old female ingested 20-30 mL of 99% chloroform solution, which caused rapid loss of consciousness, transient hypotension and severe respiratory depression requiring endotracheal intubation and ventilation. She was alert by 12 h and extubated 16 h post-overdose. At 38-h post-ingestion, her liver function tests started to rise and she was commenced on intravenous acetylcysteine. Her alanine transaminase (1283 U/L), aspartate transaminase (734 U/L) and international normalized ratio (2.3) peaked 67- to 72-h post-ingestion. She also developed severe abdominal pain, vomiting and diarrhoea. An abdominal CT scan was consistent with severe enterocolitis, and an upper gastrointestinal endoscopy showed erosive oesophagitis, severe erosive gastritis and ulceration. She was treated with opioid analgesia, proton pump inhibitors, sucralfate and total parenteral nutrition. Secretions caused a contact dermatitis of her face and back. Nine days post-ingestion she was able to tolerate food. Her liver function tests normalized and the dermatitis resolved. Chloroform was measured using headspace gas chromatograph mass spectrometry, with a peak concentration of 2.00 μg/mL, 4 h 20 min post-ingestion. The concentration-time data fitted a 1-compartment model with elimination half-life 6.5 h. In addition to early CNS depression and delayed hepatotoxicity, we report severe gastrointestinal injury and dermatitis with chloroform ingestion. Recovery occurred with good supportive care, acetylcysteine and management of gastrointestinal complications.

  17. Type 2 diabetic rats are sensitive to thioacetamide hepatotoxicity

    International Nuclear Information System (INIS)

    Sawant, Sharmilee P.; Dnyanmote, Ankur V.; Warbritton, Alan; Latendresse, John R.; Mehendale, Harihara M.

    2006-01-01

    Previously, we reported high hepatotoxic sensitivity of type 2 diabetic (DB) rats to three dissimilar hepatotoxicants. Additional work revealed that a normally nonlethal dose of CCl 4 was lethal in DB rats due to inhibited compensatory tissue repair. The present study was conducted to investigate the importance of compensatory tissue repair in determining the final outcome of hepatotoxicity in diabetes, using another structurally and mechanistically dissimilar hepatotoxicant, thioacetamide (TA), to initiate liver injury. A normally nonlethal dose of TA (300 mg/kg, ip), caused 100% mortality in DB rats. Time course studies (0 to 96 h) showed that in the non-DB rats, liver injury initiated by TA as assessed by plasma alanine or aspartate aminotransferase and hepatic necrosis progressed up to 48 h and regressed to normal at 96 h resulting in 100% survival. In the DB rats, liver injury rapidly progressed resulting in progressively deteriorating liver due to rapidly expanding injury, hepatic failure, and 100% mortality between 24 and 48 h post-TA treatment. Covalent binding of 14 C-TA-derived radiolabel to liver tissue did not differ from that observed in the non-DB rats, indicating similar bioactivation-based initiation of hepatotoxicity. S-phase DNA synthesis measured by [ 3 H]-thymidine incorporation, and advancement of cells through the cell division cycle measured by PCNA immunohistochemistry, were substantially inhibited in the DB rats compared to the non-DB rats challenged with TA. Thus, inhibited cell division and compromised tissue repair in the DB rats resulted in progressive expansion of liver injury culminating in mortality. In conclusion, it appears that similar to type 1 diabetes, type 2 diabetes also increases sensitivity to dissimilar hepatotoxicants due to inhibited compensatory tissue repair, suggesting that sensitivity to hepatotoxicity in diabetes occurs in the absence as well as presence of insulin

  18. Food Color Induced Hepatotoxicity in Swiss Albino Rats, Rattus norvegicus

    OpenAIRE

    Saxena, Beenam; Sharma, Shiv

    2015-01-01

    Objective: Certain dietary constituents can induce toxicity and play a critical role in the development of several hepatic disorders. Tartrazine, metanil yellow and sunset yellow are widely used azo dyes in food products, so the present study is aimed to investigate the food color induced hepatotoxicity in Swiss albino rats. Materials and Methods: Swiss albino rats were divided into four groups, each group having six animals. Group I served as control, Group II, Group III and Group IV were ad...

  19. [Hepatotoxicity in healthy infants exposed to nevirapine during pregnancy].

    Science.gov (United States)

    Iveli, Pablo; Noguera-Julian, Antoni; Soler-Palacín, Pere; Martín-Nalda, Andrea; Rovira-Girabal, Núria; Fortuny-Guasch, Clàudia; Figueras-Nadal, Concepció

    2016-01-01

    The use of nevirapine in HIV-infected pregnant women is discouraged due to its potential to cause hepatotoxicity. There is limited information available on the toxicity in non-HIV infected newborn exposed to this drug during pregnancy. The aim of the study is to determine the extent of hepatotoxicity in the newborn exposed to nevirapine and HIV during pregnancy. A cross-sectional, observational, multicenter study was conducted on a cohort of healthy infants born to HIV-infected mothers, in whom the first determination of alanine aminotransferase (ALT), before 6weeks of age, was collected. Patients were allocated to 2groups according to exposure to nevirapine during pregnancy. Hepatotoxicity was rated according to the AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS). This study included 160newborns from 159pregnancies (88exposed to nevirapine-based regimens and 71 exposed to protease inhibitors-based therapies). No cases of hepatotoxicity were observed according to the DAIDS Table for Grading. Two cases of ALT above normal values (2.8%; 95%CI: 0.3-9.8%) were observed in patients not exposed to nevirapine, and one case (1.1%; 95%CI: 0.0-6.1%) in the group exposed to nevirapine (P=.585). The lack of differences between groups suggests that highly active antiretroviral treatment regimens including nevirapine administered during pregnancy do not involve a higher risk of liver disease compared to other treatment combinations. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  20. Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests.

    Science.gov (United States)

    Teschke, Rolf; Frenzel, Christian; Schulze, Johannes; Schwarzenboeck, Alexander; Eickhoff, Axel

    2013-07-27

    To analyze the validity of applied test criteria and causality assessment methods in assumed Herbalife hepatotoxicity with positive reexposure tests. We searched the Medline database for suspected cases of Herbalife hepatotoxicity and retrieved 53 cases including eight cases with a positive unintentional reexposure and a high causality level for Herbalife. First, analysis of these eight cases focused on the data quality of the positive reexposure cases, requiring a baseline value of alanine aminotransferase (ALT) Herbalife in these eight cases were probable (n = 1), unlikely (n = 4), and excluded (n = 3). Confounding variables included low data quality, alternative diagnoses, poor exclusion of important other causes, and comedication by drugs and herbs in 6/8 cases. More specifically, problems were evident in some cases regarding temporal association, daily doses, exact start and end dates of product use, actual data of laboratory parameters such as ALT, and exact dechallenge characteristics. Shortcomings included scattered exclusion of hepatitis A-C, cytomegalovirus and Epstein Barr virus infection with only globally presented or lacking parameters. Hepatitis E virus infection was considered in one single patient and found positive, infections by herpes simplex virus and varicella zoster virus were excluded in none. Only one case fulfilled positive reexposure test criteria in initially assumed Herbalife hepatotoxicity, with lower CIOMS based causality gradings for the other cases than hitherto proposed.

  1. TAMH: A Useful In Vitro Model for Assessing Hepatotoxic Mechanisms

    Directory of Open Access Journals (Sweden)

    Madison Davis

    2016-01-01

    Full Text Available In vitro models for hepatotoxicity can be useful tools to predict in vivo responses. In this review, we discuss the use of the transforming growth factor-α transgenic mouse hepatocyte (TAMH cell line, which is an attractive model to study drug-induced liver injury due to its ability to retain a stable phenotype and express drug-metabolizing enzymes. Hepatotoxicity involves damage to the liver and is often associated with chemical exposure. Since the liver is a major site for drug metabolism, drug-induced liver injury is a serious health concern for certain agents. At the molecular level, various mechanisms may protect or harm the liver during drug-induced hepatocellular injury including signaling pathways and endogenous factors (e.g., Bcl-2, GSH, Nrf2, or MAPK. The interplay between these and other pathways in the hepatocyte can change upon drug or drug metabolite exposure leading to intracellular stress and eventually cell death and liver injury. This review focuses on mechanistic studies investigating drug-induced toxicity in the TAMH line and how alterations to hepatotoxic mechanisms in this model relate to the in vivo situation. The agents discussed herein include acetaminophen (APAP, tetrafluoroethylcysteine (TFEC, flutamide, PD0325901, lapatinib, and flupirtine.

  2. No evidence demonstrating hepatotoxicity associated with hydroxycitric acid

    Institute of Scientific and Technical Information of China (English)

    Sidney J Stohs; Harry G Preuss; Sunny E Ohia; Gilbert R Kaats; Carl L Keen; Lonnie D Williams; George A Burdock

    2009-01-01

    Although a number of cases of hepatotoxicity are associated with the use of Hydroxycut weight management products,it has been alleged that their effects are primarily due to the presence of hydroxycitric acid (HCA,as Super CitriMax) in the formulations.However,while these products contain up to 20 different ingredients,some do not contain HCA.Case studies reported to date have not considered in depth the literature on the numerous animal and human studies that have been conducted on the safety and efficacy of HCA.No HCAassociated hepatotoxicity or treatment-related adverse effects have been reported in these studies,and thus it is premature to make the assumptions presented in the recent case studies regarding Hydroxycut.If it is established in well controlled studies that the use of these formulations with and/or without HCA can result in the occurrence or progression of hepatotoxicity,additional studies should be conducted to characterize the causative factor(s).

  3. Rocuronium is more hepatotoxic than succinylcholine in vitro.

    Science.gov (United States)

    Sauer, Martin; Piel, Ines; Haubner, Cristof; Richter, Georg; Mann, Miriam; Nöldge-Schomburg, Gabriele; Mencke, Thomas

    2017-09-01

    The development of liver failure is a major problem in critically ill patients. The hepatotoxicity of many drugs, as one important reason for liver failure, is poorly screened for in human models. Rocuronium and succinylcholine are neuromuscular blocking agents used for tracheal intubation and for rapid-sequence induction. We used an in-vitro test with a permanent cell line and compared rocuronium and succinylcholine for hepatotoxicity. In-vitro study. A basic science laboratory, University Hospital Rostock, Germany. The basic test compound is the permanent human liver cell line HepG2/C3A. In a standardised microtitre plate assay the toxicity of different concentrations of rocuronium, succinylcholine and plasma control was tested. After two incubation periods of 3 days, the viability of cells (XTT test, lactate dehydrogenase release and trypan blue staining), micro-albumin synthesis and the cytochrome 1A2 activity (metabolism of ethoxyresorufin) were measured. Differences between rocuronium and succinylcholine were assessed using the Kruskal-Wallis one-way test and two-tailed Mann-Whitney U test. Rocuronium, but not succinylcholine, led to a significant dose-dependent decrease of viability, albumin synthesis and cytochrome 1A2 activity of test cells. An in-vitro test with a cell line showed hepatotoxicity of rocuronium that was dose-dependent. Further studies are needed to investigate the underlying mechanisms of the effects of rocuronium on hepatic cellular integrity. Not suitable.

  4. Histomorphological effects of isoniazid induced hepatotoxicity in male albino mice

    International Nuclear Information System (INIS)

    Humayun, F.; Zareen, N.

    2017-01-01

    To observe the histomorphological changes of isoniazid induced hepatotoxicity in male albino mice. Methodology: This experimental study was carried out at University of Health Sciences, Lahore, Pakistan from January to December 2013. Forty male albino mice selected by simple random technique, were divided into two groups; A-Control, and B-experimental. Group A comprised of 15, while Group B comprised 25 mice. Both the groups were kept under identical conditions and diet. However, experimental group was treated with an additional oral hepatotoxic dose of isoniazid i.e. 100mg/kg bodyweight daily for 30 days. After 30 days, the animals were sacrificed and livers were dissected out. Gross comparison of the organ and stained sections were histologically compared for morphological differences between the groups. Fischer Exact test was used to analyze the qualitative data and a p<0.05 was considered significant. Results: Group A animals showed the normal liver architecture. Whereas, those of Group B showed deranged hepatic histomorphology. Conclusion: Hepatotoxic dose of Isoniazid caused histomorphological alterations in the liver of male albino mice. (author)

  5. Hepatotoxicity induced by methimazole in a previously healthy patient.

    Science.gov (United States)

    Gallelli, Luca; Staltari, Orietta; Palleria, Caterina; De Sarro, Giovambattista; Ferraro, Maria

    2009-09-01

    We report a case of hepatotoxicity induced by methimazole treatment in a patient affected by hyperthyroidism. A 54-year-old man, presented to our observation for palpitations, excessive sweating, weakness, heat intolerance and weight loss. On physical examination, his blood pressure was 140/90 mmHg and heart beat was 100/min regular. He had mild tremors and left exophthalmos. Laboratory test revealed a significant increase in serum thyroid hormone levels with a decrease in thyroid stimulating hormone levels. A diagnosis of hyperthyroidism was made and he began treatment with methimazole (30 mg/day). Fourteen days later, he returned for the development of scleral icterus, followed by dark urine, and abdominal pain in the right upper quadrant. Laboratory examinations and liver biopsy performed a diagnosis of cholestatic hepatitis, secondary to methimazole usage. Methimazole was promptly withdrawn and cholestyramine, ursodeoxycholic acid, and chlorpheniramine were given. After five days, abdominal pain resolved and laboratory parameters returned to normal. Naranjo probability scale indicated a probable relationship between hepatotoxicity and methimazole therapy. In conclusion physicians should be aware the risk of hepatotoxicity related with methimazole.

  6. Hepatotoxic potential of asarones: In vitro evaluation of hepatotoxicity and quantitative determination in herbal products

    Directory of Open Access Journals (Sweden)

    Dhavalkumar Narendrabha Patel

    2015-02-01

    Full Text Available α and β asarones are natural constituents of some aromatic plants, especially species of the genus Acorus. In addition to beneficial properties of asarones, genotoxicity and carcinogenicity are also reported. Due to potential toxic effects of β-asarone, a limit of exposure from herbal products of approximately 2 μg/kg body weight/day has been set temporarily until a full benefit/risk assessment has been carried out by the European Medicines Agency. Therefore, it is important to monitor levels of β-asarone in herbal products. In this study, we developed a simple, rapid and validated GC-MS method for quantitative determination of asarones and applied it in 20 pediatric herbal products after detecting high concentrations of β-asarone in a product suspected to be implicated in hepatotoxicity in a 3 month old infant. Furthermore, targeted toxicological effects were further investigated in human hepatocytes (THLE-2 cells by employing various in vitro assays, with the goal of elucidating possible mechanisms for the observed toxicity. Results showed that some of the products contained as much as 4 to 25 times greater amounts of β-asarone than the recommended levels. In 4 of 10 samples found to contain asarones, the presence of asarones could not be linked to the labeled ingredients, possibly due to poor quality control. Cell-based investigations in THLE2 cells confirmed the cytotoxicity of -asarone (IC50 = 40.0 ± 2.0 µg/mL which was associated with significant lipid peroxidation and glutathione depletion. This observed cytotoxicity effect is likely due to induction of oxidative stress by asarones. Overall, the results of this study ascertained the usability of this GC-MS method for the quantitative determination of asarones from herbal products, and shed light on the importance of controlling the concentration of potentially toxic asarones in herbal products to safeguard consumer safety. Further investigations of the toxicity of asarones are

  7. Construction and analysis of a human hepatotoxicity database suitable for QSAR modeling using post-market safety data

    International Nuclear Information System (INIS)

    Zhu, Xiao; Kruhlak, Naomi L.

    2014-01-01

    Graphical abstract: - Abstract: Drug-induced liver injury (DILI) is one of the most common drug-induced adverse events (AEs) leading to life-threatening conditions such as acute liver failure. It has also been recognized as the single most common cause of safety-related post-market withdrawals or warnings. Efforts to develop new predictive methods to assess the likelihood of a drug being a hepatotoxicant have been challenging due to the complexity and idiosyncrasy of clinical manifestations of DILI. The FDA adverse event reporting system (AERS) contains post-market data that depict the morbidity of AEs. Here, we developed a scalable approach to construct a hepatotoxicity database using post-market data for the purpose of quantitative structure–activity relationship (QSAR) modeling. A set of 2029 unique and modelable drug entities with 13,555 drug-AE combinations was extracted from the AERS database using 37 hepatotoxicity-related query preferred terms (PTs). In order to determine the optimal classification scheme to partition positive from negative drugs, a manually-curated DILI calibration set composed of 105 negatives and 177 positives was developed based on the published literature. The final classification scheme combines hepatotoxicity-related PT data with supporting information that optimize the predictive performance across the calibration set. Data for other toxicological endpoints related to liver injury such as liver enzyme abnormalities, cholestasis, and bile duct disorders, were also extracted and classified. Collectively, these datasets can be used to generate a battery of QSAR models that assess a drug's potential to cause DILI

  8. The Protective Effect of Liquorice Plant Extract on CCl4-Induced Hepatotoxicity in Common Carp (Cyprinus carpio

    Directory of Open Access Journals (Sweden)

    Hassan Malekinejad

    2010-12-01

    Full Text Available The protective effect of liquorice plant extract (LPE on CCl4-induced hepatotoxicity in common carp was evaluated using fifty adult carps. The fish were cultured in a standard environment in terms of water flow rate, oxygen, pH, food and temperature. The fish were assigned into 5 groups (N = 10 as control, sham, and tests. The test groups were pre-treated for 3 h with various concentrations of LPE, 3 days before CCl4 exposure. The control and sham groups received normal saline before and after CCl4 exposure. To induce hepatotoxicity, animals in the sham and test groups were exposed against 100 l L-1 CCl4 for 45 min. The fish in all groups 1 h after CCl4 exposure were anesthetized and the blood samples were collected. Immediately the liver specimens were dissected out and were stored in 10 % formalin for further pathological studies. Determination of serum level of ALP and SGOT revealed that acute form of CCl4 exposure elevated significantly (P < 0.05 the serum level of either tested hepatic marker enzymes. While 3 days pretreatment with LPE prevented from ALP and SGOT enhancement. The pathological evaluation revealed that the CCl4 exposure resulted in a minor pathologic manifestation such as slight congestion, which the LPE pretreated groups showed the remarkable improvement. The anti-oxidant capacity of LPE was assayed by FRAP and DPPH methods. Both provided techniques showed that LPE exerts an excellent anti-oxidant effect. This data suggest that LPE exerts protective effect against CCl4-induced hepatotoxicity. Moreover, the hepatoprotective effect of LPE may attribute to its antioxidant capacity.

  9. In vivo assessment of the hepatotoxicity of a new Nostoc isolate from the Nile River: Nostoc sp. strain NRI.

    Science.gov (United States)

    Abu-Serie, Marwa M; Nasser, Nermine; Abd El-Wahab, Abeer; Shehawy, Rehab; Pienaar, Harrison; Baddour, Nahed; Amer, Ranya

    2018-03-01

    Nostoc sp. is one of the most widely distributed cyanobacterial genera that produce potentially protein phosphatase (PP) inhibitor; microcystins (MCs). MCs have posed a worldwide concern due to predominant hepatotoxicity to human health. We have previously isolated a Nostoc strain (NR1) from the Nile River (the main water supply in Egypt) and this strain exerted production of rare and highly toxic MC; demethylated microcystin-LR. There is no data concerning risk factors of liver diseases for human and animal exposure to NR1-contaminated drinking water yet. It is thus important to evaluate acute (LD 50 dose), subacute (0.01% and 10% of LD 50 dose) and subchronic (0.01% and 10% of LD 50 dose) hepatotoxicity's NR1 extract using experimental mice. Mice groups, who orally received 0.01% LD 50 , represented a permissible concentration of the World Health Organization (WHO) for MC in drinking water. Several parameters were detected, including hepatotoxicity (i.e. PP activity, liver function, oxidative stress markers and DNA fragmentation), pro-inflammatory cytokine (TNF-α) and liver histopathology. Our results demonstrated LD 50 of NR1 extract was at 15,350 mg/kg body weight and caused hepatotoxicity that attributed to PP inhibition and a significant increase of hepatic damage biomarkers with lipid accumulation. Moreover, NR1 extract induced hepatic oxidative damage that may have led to DNA fragmentation and production of TNF-α. As demonstrated from the histopathological study, NR1 extract caused a severe collapse of cytoskeleton with subsequent focal degeneration of hepatocytes, necroinflammation and steatosis. The grade of hepatotoxicity in subacute (10% of LD 50 ) group was higher than that in the subchronic (10% of LD 50 and 0.01% of LD 50 , WHOch, respectively) groups. No significant hepatotoxicity was detectable for subacute (0.01% of LD 50 , WHOac) group. NR1 is therefore considered as one of the harmful and life-threatening cyanobacteria for Egyptian people

  10. Determination of the Antiproliferative Activity of New Theobromine Derivatives and Evaluation of Their In Vitro Hepatotoxic Effects.

    Science.gov (United States)

    Georgieva, Maya; Kondeva-Burdina, Magdalena; Mitkov, Javor; Tzankova, Virginia; Momekov, Georgi; Zlatkov, Alexander

    2016-01-01

    A new series of N-substituted 1-benzyltheobromine-8-thioacetamides were designed and synthesized. Their anti-proliferative activity against human chronic myelocytic leukemia cell K562, human T-cell leukemia cell SKW-3 and human acute myeloid leukemia HL-60 was evaluated. For the tested compounds a concentrationdependent cytotoxic activity was observed, with 7g outlined as the most active compound within the series. The targed compounds were obtained in yields of 56 to 85% and their structures were elucidated by FTIR, (1)H NMR, (13)C NMR and microanalyses. The compounds purity was proven by elemental analysis and spectral data. In general, the compounds showed low hepatotoxicity on sub-cellular and cellular level. On isolated rat microsomes only 7d showed toxic effect while theobromine, 1-benzyl-theobromine-thioacetic acid (BTTA) and the other new theobromine derivatives were devoid of toxicity. In isolated rat hepatocytes, when compared to theobromine and BTTA, 7f showed lower cytotoxic effects, and 7d exerted higher cytotoxicity. The results indicate 7g as a promising structure for the design of future compounds with low hepatotoxicity and good antiproliferative activity.

  11. The combination of atorvastatin and ethanol is not more hepatotoxic to rats than the administration of each drug alone

    Directory of Open Access Journals (Sweden)

    D.T. Ito

    2007-03-01

    Full Text Available Animal studies and premarketing clinical trials have revealed hepatotoxicity of statins, primarily minor elevations in serum alanine aminotransferase levels. The combined chronic use of medicines and eventual ethanol abuse are common and may present a synergistic action regarding liver injury. Our objective was to study the effect of the chronic use of atorvastatin associated with acute ethanol administration on the liver in a rat model. One group of rats was treated daily for 5 days a week for 2 months with 0.8 mg/kg atorvastatin by gavage. At the end of the treatment the livers were perfused with 72 mM ethanol for 60 min. Control groups (at least 4 animals in each group consisted of a group of 2-month-old male Wistar EPM-1 rats exposed to 10% ethanol (v/v ad libitum replacing water for 2 months, followed by perfusion of the liver with 61 nM atorvastatin for 60 min, and a group of animals without chronic ethanol treatment whose livers were perfused with atorvastatin and/or ethanol. The combination of atorvastatin with ethanol did not increase the release of injury marker enzymes (alanine aminotransferase, aspartate aminotransferase, and lactic dehydrogenase from the liver and no change in liver function markers (bromosulfophthalein clearance, and oxygen consumption was observed. Our results suggest that the combination of atorvastatin with ethanol is not more hepatotoxic than the separate use of each substance.

  12. Disturbance of gene expression in primary human hepatocytes by hepatotoxic pyrrolizidine alkaloids: A whole genome transcriptome analysis.

    Science.gov (United States)

    Luckert, Claudia; Hessel, Stefanie; Lenze, Dido; Lampen, Alfonso

    2015-10-01

    1,2-unsaturated pyrrolizidine alkaloids (PA) are plant metabolites predominantly occurring in the plant families Asteraceae and Boraginaceae. Acute and chronic PA poisoning causes severe hepatotoxicity. So far, the molecular mechanisms of PA toxicity are not well understood. To analyze its mode of action, primary human hepatocytes were exposed to a non-cytotoxic dose of 100 μM of four structurally different PA: echimidine, heliotrine, senecionine, senkirkine. Changes in mRNA expression were analyzed by a whole genome microarray. Employing cut-off values with a |fold change| of 2 and a q-value of 0.01, data analysis revealed numerous changes in gene expression. In total, 4556, 1806, 3406 and 8623 genes were regulated by echimidine, heliotrine, senecione and senkirkine, respectively. 1304 genes were identified as commonly regulated. PA affected pathways related to cell cycle regulation, cell death and cancer development. The transcription factors TP53, MYC, NFκB and NUPR1 were predicted to be activated upon PA treatment. Furthermore, gene expression data showed a considerable interference with lipid metabolism and bile acid flow. The associated transcription factors FXR, LXR, SREBF1/2, and PPARα/γ/δ were predicted to be inhibited. In conclusion, though structurally different, all four PA significantly regulated a great number of genes in common. This proposes similar molecular mechanisms, although the extent seems to differ between the analyzed PA as reflected by the potential hepatotoxicity and individual PA structure. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Effect of anemia on hepatotoxicity of HAART in HIV patients in Benin ...

    African Journals Online (AJOL)

    Background: Hepatotoxicity is a relevant adverse effect of highly active antiretroviral Treatment owing to its frequency, and it can cause interruption of therapy, hepatitis, and death. There is dearth of information on hepatotoxicity arising from highly active antiretroviral therapy (HAART) in anemic patients. Anemia is the most ...

  14. Herbal hepatotoxicity: suspected cases assessed for alternative causes.

    Science.gov (United States)

    Teschke, Rolf; Schulze, Johannes; Schwarzenboeck, Alexander; Eickhoff, Axel; Frenzel, Christian

    2013-09-01

    Alternative explanations are common in suspected drug-induced liver injury (DILI) and account for up to 47.1% of analyzed cases. This raised the question of whether a similar frequency may prevail in cases of assumed herb-induced liver injury (HILI). We searched the Medline database for the following terms: herbs, herbal drugs, herbal dietary supplements, hepatotoxic herbs, herbal hepatotoxicity, and herb-induced liver injury. Additional terms specifically addressed single herbs and herbal products: black cohosh, Greater Celandine, green tea, Herbalife products, Hydroxycut, kava, and Pelargonium sidoides. We retrieved 23 published case series and regulatory assessments related to hepatotoxicity by herbs and herbal dietary supplements with alternative causes. The 23 publications comprised 573 cases of initially suspected HILI; alternative causes were evident in 278/573 cases (48.5%). Among them were hepatitis by various viruses (9.7%), autoimmune diseases (10.4%), nonalcoholic and alcoholic liver diseases (5.4%), liver injury by comedication (DILI and other HILI) (43.9%), and liver involvement in infectious diseases (4.7%). Biliary and pancreatic diseases were frequent alternative diagnoses (11.5%), raising therapeutic problems if specific treatment is withheld; pre-existing liver diseases including cirrhosis (9.7%) were additional confounding variables. Other diagnoses were rare, but possibly relevant for the individual patient. In 573 cases of initially assumed HILI, 48.5% showed alternative causes unrelated to the initially incriminated herb, herbal drug, or herbal dietary supplement, calling for thorough clinical evaluations and appropriate causality assessments in future cases of suspected HILI.

  15. Potential protective effect of honey against paracetamol-induced hepatotoxicity.

    Science.gov (United States)

    Galal, Reem M; Zaki, Hala F; Seif El-Nasr, Mona M; Agha, Azza M

    2012-11-01

    Paracetamol overdose causes severe hepatotoxicity that leads to liver failure in both humans and experimental animals. The present study investigates the protective effect of honey against paracetamol-induced hepatotoxicity in Wistar albino rats. We have used silymarin as a standard reference hepatoprotective drug. Hepatoprotective activity was assessed by measuring biochemical parameters such as the liver function enzymes, serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST). Equally, comparative effects of honey on oxidative stress biomarkers such as malondialdyhyde (MDA), reduced glutathione (GSH) and glutathione peroxidase (GPx) were also evaluated in the rat liver homogenates.  We estimated the effect of honey on serum levels and hepatic content of interleukin-1beta (IL-1β) because the initial event in paracetamol-induced hepatotoxicity has been shown to be a toxic-metabolic injury that leads to hepatocyte death, activation of the innate immune response and upregulation of inflammatory cytokines. Paracetamol caused marked liver damage as noted by significant increased activities of serum AST and ALT as well as the level of Il-1β. Paracetamol also resulted in a significant decrease in liver GSH content and GPx activity which paralleled an increase in Il-1β and MDA levels. Pretreatment with honey and silymarin prior to the administration of paracetamol significantly prevented the increase in the serum levels of hepatic enzyme markers, and reduced both oxidative stress and inflammatory cytokines. Histopathological evaluation of the livers also revealed that honey reduced the incidence of paracetamol-induced liver lesions. Honey can be used as an effective hepatoprotective agent against paracetamol-induced liver damage.

  16. Incidence and risk of regorafenib-induced hepatotoxicity.

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    Zhao, Bin; Zhao, Hong

    2017-10-13

    Regorafenib, an oral multi-kinase inhibitor, has been approved for the treatments of several malignancies. Unlike traditional cytotoxic chemotherapeutic agents, regorafenib therapy often induces a distinct profile of adverse events (AEs) including hepatotoxicity. Here we conducted an up-to-date meta-analysis to assess the incidence and risk of regorafenib related hepatic toxicities. PubMed and Embase database were reviewed from inception to June 2017 for relevant trials. Eligible studies include subjects with solid tumors treated with 160 mg of regorafenib daily during the first three week of each four-week cycle, and adequate safety data reporting the elevation of aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and bilirubin. Statistical analyses were conducted to calculate the summary incidence and relative risk (RR). A total of 2,213 subjects from 14 trials were included. The incidences of regorafenib-associated all-grade and high-grade hepatotoxicity were: bilirubin elevation: 23% and 5%; AST elevation: 32% and 6%; ALT elevation: 27% and 5%; ALP elevation: 31% and 2%. Regorafenib-treated subjects had a significant increased risk of all-grade (RR = 3.10; 95% CI, 2.22-4.34) and high-grade (RR = 1.74; 95% CI, 1.09-2.80) bilirubin elevation; all-grade (RR = 1.51; 95% CI, 1.13-2.00) and high-grade (RR = 1.79; 95% CI, 1.00-3.22) AST elevation; all-grade (RR = 1.82; 95% CI, 1.25-2.64) and high-grade (RR = 3.07; 95% CI, 1.30-7.22) ALT elevation; and all-grade (RR = 2.11; 95% CI, 1.01-4.40) ALP elevation. Our results suggest that regorafenib is associated with an increased risk of hepatic toxicities. Hepatotoxicity examination at regular intervals should be advised to clinicians.

  17. Antioxidant modulation of nevirapine induced hepatotoxicity in rats

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    Awodele Olufunsho

    2015-03-01

    Full Text Available HIV/AIDS related mortality has been dramatically reduced by the advent of antiretroviral therapy (ART. However, ART presents with associated adverse effects. One of such adverse effects is hepatotoxicity observed with nevirapine (NVP containing ART. Since previous studies showed that NVP hepatotoxicity may be due to oxidative stress via generation of oxidative radicals, this study sought to evaluate the protective effects of antioxidants in alleviating NVP induced hepatotoxicity. Rats were divided into 6 groups with 8 animals per group and received doses of the antioxidants jobelyn (10.7 mg/kg/day, vitamin C (8 mg/kg/day, vitamin E (5 mg/kg/day and/or NVP (6 mg/kg/day for 60 days. The animals were sacrificed on day 61 by cervical dislocation, blood samples were collected for biochemical and hematological examination. The liver of the sacrificed animals was weighed and subjected to histopathological examination. There was a statistically significant (p<0.05 elevation in MDA level observed in the NVP group as compared with control. The results further showed non-significant decreases in the levels of MDA in the NVP plus antioxidant groups, except vitamin C, when compared with the NVP alone group. Vitamin E and Vitamin E plus C treated groups showed significantly (p<0.05 higher levels of SOD, CAT and GSH. The results also showed statistically significantly (p<0.05 lower levels of ALT and AST in the antioxidant treated groups There was an observed significantly (p<0.05 higher level of TP and urea in the antioxidant treated rats. A significantly (p<0.05 higher white blood cell count was observed in the antioxidant groups. Histopathological assessment of the liver extracted from the rats showed no visible pathology across the groups. Observations from this study suggest a potentially positive modulatory effect of antioxidants and may be indicative for the inclusion of antioxidants in nevirapine containing ART.

  18. Hepato-toxic effect of diuron in albino rats.

    Science.gov (United States)

    Agrawal, R C; Kumar, S

    1999-05-01

    Tumour initiating/promoting effect of diuron, a widely used substituted urea herbicide, was studied in rats using liver tumour model. Chronic exposure to diuron at a dose of 250 mg/kg body wt resulted in high mortality and weight loss in treated animals. The animals which received diuron + HCH treatment showed an increase in size and weight of liver as compared to controls. Liver tumours were not observed in any of the treated group whereas some significant histological changes were seen in diuron treated rat liver. Diuron thus has been found to be hepatotoxic albeit neither tumour initiating nor promoting in rat liver tumorigenesis assay system.

  19. Curcumin Attenuates Hepatotoxicity Induced by Zinc Oxide Nanoparticles in Rats

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    Layasadat Khorsandi

    2016-06-01

    Full Text Available Background: Zinc oxide nanoparticles (NZnO are increasingly used in modern life. Most metal nanoparticles have adverse effects on the liver. Aims: To explore the protective action of curcumin (Cur against hepatotoxicity induced by NZnO in rats. Study Design: Animal experimentation. Methods: Control group animals received normal saline, while the Cur group animals were treated with 200 mg/kg of Cur orally for 21 days. NZnO-intoxicated rats received 50 mg/kg of NZnO for 14 days by gavage method. In the NZnO+Cur group, rats were pretreated with Cur for 7 days before NZnO administration. Plasma activities of Alanine aminotransferase (ALT, aspartate aminotransferase (AST and alkaline phosphatase (ALP were measured as biomarkers of hepatotoxicity. Hepatic levels of malondialdehyde (MDA and superoxide dismutase (SOD and glutathione peroxidase (GPx activities were measured for detection of oxidative stress in liver tissue. Histological changes and apoptosis in liver tissue were studied by using Hematoxylin-eosin staining and the transferase dUTP nick end labeling (TUNEL method. Results: NZnO induced a significant increase in plasma AST (2.8-fold, ALT (2.7-fold and ALP (1.97-fold activity in comparison to the control group (p<0.01. NZnO increased MDA content and reduced SOD and GPx activities. NZnO caused liver damage including centrilobular necrosis and microvesicular steatosis. The percentage of apoptosis in hepatocytes was increased in NZnO-treated rats (p<0.01. Pre-treatment of Cur significantly reduced lipid peroxidation (39%, increased SOD (156% and GPx (26% activities, and attenuated ALT (47%, AST (41% and ALP (30% activities. Pre-treatment with Cur also decreased the histology changes and apoptotic index of hepatocytes (p<0.05. Conclusion: These findings indicate that Cur effectively protects against NZnO-induced hepatotoxicity in rats. However, future studies are required to propose Cur as a potential protective agent against hepatotoxicity

  20. Acute interstitial nephritis with acetaminophen and alcohol intoxication

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    Alexopoulou Iakovina

    2011-04-01

    Full Text Available Abstract Drug-induced acute interstitial nephritis (AIN represents a growing cause of renal failure in current medical practice. While antimicrobials and non-steroidal anti-inflammatory drugs are typically associated with drug-induced AIN, few reports have been made on the involvement of other analgesics. We report our experience in managing a 17-year-old female with AIN and subsequent renal injury following an acetaminophen overdose in conjunction with acute alcohol intoxication. It is well established that acetaminophen metabolism, particularly at high doses, produces reactive metabolites that may induce renal and hepatic toxicity. It is also plausible however, that such reactive species could instead alter renal peptide immunogenicity, thereby inducing AIN. In the following report, we review a possible mechanism for the acetaminophen-induced AIN observed in our patient and also discuss the potential involvement of acute alcohol ingestion in disease onset. The objective of our report is to increase awareness of healthcare professionals to the potential involvement of these commonly used agents in AIN pathogenesis.

  1. Bisphenol A Induces Hepatotoxicity through Oxidative Stress in Rat Model

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    Zeinab K. Hassan

    2012-01-01

    Full Text Available Reactive oxygen species (ROS are cytotoxic agents that lead to significant oxidative damage. Bisphenol A (BPA is a contaminant with increasing exposure to it and exerts both toxic and estrogenic effects on mammalian cells. Due to limited information concerning the effect of BPA on liver, this study investigates whether BPA causes hepatotoxicity by induction of oxidative stress in liver. Rats were divided into five groups: The first four groups, BPA (0.1, 1, 10, 50 mg/kg/day were administrated orally to rats for four weeks. The fifth group was taken water with vehicle. The final body weights in the 0.1 mg group showed a significant decrease compared to control group. Significant decreased levels of reduced glutathione, superoxide dismutase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase and catalase activity were found in the 50 mg BPA group compared to control groups. High dose of BPA (50 mg/kg significantly increased the biochemical levels of ALT, ALP and total bilirubin. BPA effect on the activity of antioxidant genes was confirmed by real time PCR in which the expression levels of these genes in liver tissue were significantly decrease compared to control. Data from this study demonstrate that BPA generate ROS and reduce the antioxidant gene expression that causes hepatotoxicity.

  2. Hepatotoxicity and nephrotoxicity of 3-bromopyruvate in mice.

    Science.gov (United States)

    Pan, Qiong; Sun, Yiming; Jin, Qili; Li, Qixiang; Wang, Qing; Liu, Hao; Zhao, Surong

    2016-11-01

    To investigate the hepatotoxicity and nephrotoxicity of 3-Bromopyruvate (3BP) in mice. Fifteen nude mice were grafted subcutaneously in the left flank with MDA-MB-231 cells, then all mice were divided into control group (PBS), 3BP group (8 mg/kg), positive group (DNR: 0.8 mg/kg) when tumor volume reached approximately 100 mm3. 28 days later, tumors, livers and kidneys were stored in 4 % formalin solution and stained with hematoxylin and eosin staining. The Kunming mice experiment included control group (PBS), 3BP group (4mg/kg; 8mg/kg; 16mg/kg), positive group (DNR: 0.8 mg/kg). 24 hours later, the blood were used for the determination of hepatic damage serum biomarkers. Livers were stored in 4 % formalin solution for the later detection. 3BP at the dose of 8mg/kg had a good effect on inhibiting tumor growth in nude mice and did not damage liver and kidney tissues. Kunming mice experiment showed 3BP at the dose of 16mg/kg did damage to liver tissues. 3-Bromopyruvate at the dose of suppressing tumor growth did not exhibit hepatotoxicity and nephrotoxicity in nude mice, and the effect on liver was confirmed in Kunming mice.

  3. Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics.

    Science.gov (United States)

    García-Cortés, Miren; Robles-Díaz, Mercedes; Ortega-Alonso, Aida; Medina-Caliz, Inmaculada; Andrade, Raul J

    2016-04-09

    Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™) while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs.

  4. Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics

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    Miren García-Cortés

    2016-04-01

    Full Text Available Dietary supplements (DS are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™ while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang. Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs.

  5. Engineered andrographolide nanosystems for smart recovery in hepatotoxic conditions

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    Roy P

    2014-10-01

    Full Text Available Partha Roy,1,2 Suvadra Das,1 Runa Ghosh Auddy,1,3 Arup Mukherjee1,3 1Division of Pharmaceutical and Fine Chemicals Technology, Department of Chemical Technology, University of Calcutta, Kolkata, India; 2Faculty of Technology (Pharmaceutical, Universiti Malaysia, Pahang, Malaysia; 3Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, Kolkata, India Abstract: Andrographolide (AG is one of the most potent labdane diterpenoid-type free radical scavengers available from plant sources. The compound is the principal bioactive component in Andrographis paniculata leaf extracts, and is responsible for anti-inflammatory, anticancer, and immunomodulatory activity. The application of AG in therapeutics, however, is severely constrained, due to its low aqueous solubility, short biological half-life, and poor cellular permeability. Engineered nanoparticles in biodegradable polymer systems were therefore conceived as one solution to aid in further drug-like applications of AG. In this study, a cationic modified poly(lactic-co-glycolic acid nanosystem was applied for evaluation against experimental mouse hepatotoxic conditions. Biopolymeric nanoparticles of hydrodynamic size of 229.7±17.17 nm and ζ-potential +34.4±1.87 mV facilitated marked restoration in liver functions and oxidative stress markers. Superior dissolution for bioactive AG, hepatic residence, and favorable cytokine regulation in the liver tissues are some of the factors responsible for the newer nanosystem-assisted rapid recovery. Keywords: andrographolide, engineered nanosystems, poly(lactic-co-glycolic acid, cytokine regulation, hepatotoxicity

  6. Food Color Induced Hepatotoxicity in Swiss Albino Rats, Rattus norvegicus.

    Science.gov (United States)

    Saxena, Beenam; Sharma, Shiv

    2015-01-01

    Certain dietary constituents can induce toxicity and play a critical role in the development of several hepatic disorders. Tartrazine, metanil yellow and sunset yellow are widely used azo dyes in food products, so the present study is aimed to investigate the food color induced hepatotoxicity in Swiss albino rats. Swiss albino rats were divided into four groups, each group having six animals. Group I served as control, Group II, Group III and Group IV were administered with 25, 50 and 75 mg/kg body weight blend of sunset yellow, metanil yellow and tartrazine for 30 days. Hepatotoxicity in rats treated with a blend of these food colors was studied by assessing parameters such as serum total protein, serum albumin, serum alkaline phosphatase (ALP) as well as hepatic malondialdehyde (MDA). The activity of superoxide dismutase (SOD), reduced glutathione (GSH) and catalase (CAT) were assessed. Significantly increased concentrations of serum total protein, serum albumin, serum ALP and hepatic MDA and significantly lowered levels of SOD, reduced GSH and CAT in the liver tissue of treated animals were observed when compared with control animals. The alteration in the liver includes necrosis of hepatocytes, infiltration and vacuolation. The result indicates that consumption of food color in diet induces liver tissue damage. The used doses of food color were mostly attributable to hepatocellular damage and drastic alteration in antioxidant defense system.

  7. Bee sting therapy-induced hepatotoxicity: A case report.

    Science.gov (United States)

    Alqutub, Adel Nazmi; Masoodi, Ibrahim; Alsayari, Khalid; Alomair, Ahmed

    2011-10-27

    The use of bee venom as a therapeutic agent for the relief of joint pains dates back to Hippocrates, and references to the treatment can be found in ancient Egyptian and Greek medical writings as well. Also known as apitherapy, the technique is widely used in Eastern Europe, Asia, and South America. The beneficial effects of bee stings can be attributed to mellitinin, an anti-inflammatory agent, known to be hundred times stronger than cortisone. Unfortunately, certain substances in the bee venom trigger allergic reactions which can be life threatening in a sensitized individual. Multiple stings are known to cause hemolysis, kidney injury, hepatotoxicity and myocardial infarction. The toxicity can be immediate or can manifest itself only weeks after the exposure. We describe hepatotoxicity in a 35-year-old female, following bee sting therapy for multiple sclerosis. She presented to our clinic 3 wk after therapy with a history of progressive jaundice. The patient subsequently improved, and has been attending our clinic now for the last 9 mo.

  8. Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics

    Science.gov (United States)

    García-Cortés, Miren; Robles-Díaz, Mercedes; Ortega-Alonso, Aida; Medina-Caliz, Inmaculada; Andrade, Raul J.

    2016-01-01

    Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™) while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs. PMID:27070596

  9. Food Color Induced Hepatotoxicity in Swiss Albino Rats, Rattus norvegicus

    Science.gov (United States)

    Saxena, Beenam; Sharma, Shiv

    2015-01-01

    Objective: Certain dietary constituents can induce toxicity and play a critical role in the development of several hepatic disorders. Tartrazine, metanil yellow and sunset yellow are widely used azo dyes in food products, so the present study is aimed to investigate the food color induced hepatotoxicity in Swiss albino rats. Materials and Methods: Swiss albino rats were divided into four groups, each group having six animals. Group I served as control, Group II, Group III and Group IV were administered with 25, 50 and 75 mg/kg body weight blend of sunset yellow, metanil yellow and tartrazine for 30 days. Hepatotoxicity in rats treated with a blend of these food colors was studied by assessing parameters such as serum total protein, serum albumin, serum alkaline phosphatase (ALP) as well as hepatic malondialdehyde (MDA). The activity of superoxide dismutase (SOD), reduced glutathione (GSH) and catalase (CAT) were assessed. Results: Significantly increased concentrations of serum total protein, serum albumin, serum ALP and hepatic MDA and significantly lowered levels of SOD, reduced GSH and CAT in the liver tissue of treated animals were observed when compared with control animals. The alteration in the liver includes necrosis of hepatocytes, infiltration and vacuolation. Conclusion: The result indicates that consumption of food color in diet induces liver tissue damage. The used doses of food color were mostly attributable to hepatocellular damage and drastic alteration in antioxidant defense system. PMID:26862277

  10. Bees’ Honey Attenuation of Metanil-Yellow-Induced Hepatotoxicity in Rats

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    Abdulrahman L. Al-Malki

    2013-01-01

    Full Text Available The present study aims to investigate the protective effect of bees’ honey against metanil-yellow-induced hepatotoxicity in rats. Rats were divided into 7 groups: control group; three groups treated with 50, 100, and 200 mg/kg metanil yellow, and three groups treated with metanil yellow plus 2.5 mg·kg-1·day-1 bees’ honey for 8 weeks. The obtained data showed that the antioxidant/anti-inflammatory activity of bees’ honey reduced the oxidative stress in the liver tissue and downregulated the inflammatory markers. In addition, the elevated levels of AGE and the activated NF-κB in the metanil-yellow-treated animals were significantly attenuated. Moreover, the levels of TNF-α and IL-1β were significantly attenuated as a result of bees’ honey administration. Furthermore, the histopathological examination of the liver showed that bees’ honey reduced fatty degeneration, cytoplasmic vacuolization, and necrosis in metanil-yellow-treated rats. In conclusion, the obtained data suggest that bees’ honey has hepatoprotective effect on acute liver injuries induced by metanil-yellow in vivo, and the results suggested that the effect of bees’ honey against metanil yellow-induced liver damage is related to its antioxidant/anti-inflammatory properties which attenuate the activation of NF-κB and its controlled genes like TNF-α and IL-1β.

  11. Oral metformin-ascorbic acid co-administration ameliorates alcohol-induced hepatotoxicity in rats.

    Science.gov (United States)

    Adeneye, A A; Benebo, A S

    2007-01-01

    Alcoholic liver disease remains a major cause of liver failure worldwide with no available curative or prophylactic therapy as at present. High dose metformin is reported to ameliorate liver injuries in both human and animal models of acute and chronic alcoholic liver injuries. The aim of the present in vivo animal study was to determine whether metformin-ascorbic acid co-administration also prevents alcoholic hepatotoxicity in chronic alcohol exposure. In the present study, ameliorating effect of 200 mg/ kg/day of ascorbic acid (Asc), 500 mg/kg/day of metformin (Met) and their co-administration (Met-Asc) were investigated in 5 groups of 50% ethanol-treated male Wistar rats for 2 weeks of the experiment. The body weight of each rat was taken on days 1, 7, and 14 of the experiment, respectively. On day 15, fasted blood samples for plasma lipids and liver enzyme markers were collected via cardiac puncture from the rats under diethyl ether anaesthesia. Results showed that administration of graded oral doses of 50% ethanol for 14 days significantly (pcholesterol (PTC), high density lipoprotein (HDL-c), and low density lipoprotein (LDL-c). However, these elevations were significantly (pascorbic acid co-administration protected the liver against the deleterious effects of chronic high dose alcohol and the hepatoprotective effect of Met-Asc appeared to be due mainly to the metformin molecule of the drug combination. However, further studies would be required to evaluate the mechanisms underlying the observed effects.

  12. Hepatotoxicity of Nonsteroidal Anti-Inflammatory Drugs: A Systematic Review of Randomized Controlled Trials

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    Pajaree Sriuttha

    2018-01-01

    Full Text Available Background. Nonsteroidal anti-inflammatory drugs (NSAIDs are the most widely used medication in several countries, including Thailand. NSAIDs have been associated with hepatic side effects; however, the frequency of these side effects is uncertain. Aim of the Review. To systematically review published literature on randomized, controlled trials that assessed the risk of clinically significant hepatotoxicity associated with NSAIDs. Methods. Searches of bibliographic databases EMBASE, PubMed, and the Cochrane Library were conducted up to July 30, 2016, to identify randomized controlled trials of ibuprofen, naproxen, diclofenac, piroxicam, meloxicam, mefenamic acid, indomethacin, celecoxib, and etoricoxib in adults with any disease that provide information on hepatotoxicity outcomes. Results. Among the 698 studies, 18 studies met the selection criteria. However, only 8 studies regarding three NSAIDs (celecoxib, etoricoxib, and diclofenac demonstrated clinically significant hepatotoxic evidence based on hepatotoxicity justification criteria. Of all the hepatotoxicity events found from the above-mentioned three NSAIDs, diclofenac had the highest proportion, which ranged from 0.015 to 4.3 (×10−2, followed by celecoxib, which ranged from 0.13 to 0.38 (×10−2, and etoricoxib, which ranged from 0.005 to 0.930 (×10−2. Conclusion. Diclofenac had higher rates of hepatotoxic evidence compared to other NSAIDs. Hepatotoxic evidence is mostly demonstrated as aminotransferase elevation, while liver-related hospitalization or discontinuation was very low.

  13. Hepatotoxicity associated with microcystin/ Hepatotoxicidade associada à microcistina

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    Ana Paula Frederico Rodrigues Loureiro Bracarense

    2008-08-01

    Full Text Available Urban and industrial discharges, intense agricultural exploitation and fisheries have been causing the eutrophication in both drinking and recreational waters. A frequent consequence of eutrophication in waters is the massive development of cyanobacteria. The occurrence of these blooms induces a severe problem, as Microcystis aeruginosa, the most widespread distributed cyanobacteria, can produce microcystins (MC. Toxic effects of MC have been described in liver, lungs, stomach, and intestine. Deaths in wildlife, livestock and human beings were also associated with MC exposition. MC exposition can occurs directly by ingestion, inhalation, contact, intravenous inoculation of contaminated water (hemodialysis or indirectly, by the consumption of animals, as fish and mollusks, the majors ingestors of cyanobacteria and its toxins. The most toxic MC, an also the most common is microcystin-LR (MC-LR, that has the liver as the main target organ. Microcystin is taken up specifically into the liver by bile acid transporters and, after entering the cytoplasm, inhibit protein phosphatases 1 and 2A, which leads to the increase in protein phosphorylation. This effect has two main consequences: the destruction of cytoskeleton directly causing cytotoxic effects, and deregulation of cell division, leading to tumor-promoting activity. Acute exposition to MC induces severe intrahepatic hemorrhage, necrosis and apoptosis, while chronic exposure can cause hepatic or intestinal neoplasia. It has been documented that MC hepatotoxicity is closely associated with intracellular reactive oxygen species formation. Natural degradation of microcystins depends on the solar radiation and bacteria. If degradation is insufficient, MC will persist in the freshwater food chain. Microcystin contamination of waters is therefore a hazard to human and animal health, so efforts to avoid eutrophication of waters sources are essential, in order to minimize the risks to public health

  14. Doxorubicin hepatotoxicity and hepatic free radical metabolism in rats

    International Nuclear Information System (INIS)

    Kalender, Yusuf; Yel, Mustafa; Kalender, Suna

    2005-01-01

    Doxorubicin (DXR) is an anthracycline antibiotic, broady used in tumor therapy. In the present study we investigated whether vitamin E and catechin can reduce the toxic effects of doxorubicin. Vitamin E (200 IU/kg/week), catechin (200 mg/kg/week), doxorubicin (5 mg/kg/week), doxorubicin + vitamin E (200 IU/kg/week), doxorubicin + catechin (200 mg/kg/week) combinations were given to rats weighing 210-230 g (n = 6/group). Changes in major enzymes participating in free radical metabolism superoxide dismutase (Cu,Zn-SOD), glutathione peroxidase (GSHPx), catalase (CAT) and malondialdehyde (MDA) were evaluated in the livers of all animals. Superoxide dismutase and catalase activity increased in the doxorubicin-treated group compared to control (P 0.05). Electron microscopic studies supported biochemical findings. We conclude that vitamin E and catechin significantly reduce doxorubicin-induced hepatotoxicity in rats

  15. Possible hepatotoxic consequence of nevirapine use in juvenile albino rats

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    Elias Adikwu

    2017-08-01

    Full Text Available Context: Nevirapine (NVP is used in human immunodeficiency virus exposed neonates. This could present safety concern due to decreased liver metabolizing enzymes activity and renal clearance in neonates. Aims: To determine the hepatotoxic effect of NVP in juvenile albino rats. Methods: Juvenile albino rats were weighed, divided into groups and treated orally with 4-32 mg/kg/day of NVP for 14 days including a recovery group. The control groups were treated with water (placebo and normal saline (solvent. At the end of NVP treatment, rats were weighed and sacrificed, blood was collected and serum extracted. Serum was analyzed for alanine aminotransferase (ALT, aspartate aminotransferase (AST, alkaline phosphatase (ALP, total bilirubin (TB and conjugated bilirubin (CB. The liver was harvested via dissection, weighed and evaluated for AST, ALT, ALP, superoxide dismutase (SOD, catalase (CAT, glutathione (GSH, malondialdehyde (MDA levels and histological damage. Results: The body, absolute and relative liver weights of rats in NVP treated groups were not significantly different (p>0.05 when compared to placebo. However, serum levels of AST, ALT, ALP, TB and CB were significantly increased (p<0.05 in a dose-dependent manner in NVP-treated groups. Furthermore, liver levels of ALT, ALP, AST and MDA were significantly increased (p<0.05 while SOD, CAT, and GSH were decreased in a dose dependent manner in NVP-treated groups. NVP-treated rats were characterized by varying degrees of hepatic morphological alterations. However, in the recovery group, the effects of NVP were reversed. Conclusions: This study observed dose-dependent and reversible hepatotoxicity in nevirapine- treated juvenile albino rats.

  16. Hepatotoxicity and genotoxicity of gasoline fumes in albino rats

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    Folarin O. Owagboriaye

    2017-09-01

    Full Text Available Toxic effects of gasoline fumes have been reported, but evidence of its hepatotoxicity and genotoxicity are rare. Therefore, this study assesses hepatotoxicity and genotoxicity of gasoline fumes on forty Albino rats randomly assigned to five experimental treatments (T with eight rats per treatment (T1, T2, T3, T4 and T5. T1(Control was housed in a section of experimental animal house free from gasoline fumes while T2, T3, T4 and T5 were exposed to gasoline fumes in exposure chambers for one, three, five and nine hours daily respectively for twelve weeks. Serum alanine aminotransferase (ALT, aspartate aminotransferase (AST, alkaline phosphatase (ALP and histopathological examination of the liver tissues were used as diagnostic markers to assess liver dysfunction. Genotoxicity test was conducted on the lung tissues using randomly amplified polymorphic DNA fingerprinting polymerase chain reaction (RAPD PCR technique. Significant increase (p < 0.05 in the level of ALT, AST and ALP for T2, T3, T4 and T5 compared to T1 were recorded. Photomicrograph examination of the liver sections of T1 showed hepatic tissue with normal liver cell architecture while that of T2, T3, T4 and T5 revealed degenerative changes in the ultrastructural integrity of the hepatic cells. Genotoxicity test revealed DNA bands at a reducing intensity from T1 to T5. Dendrogram showed DNA damage in the lungs of T3, T4 and T5 were closely similar and the genotoxic impact was more in T3. Frequent exposure to gasoline fumes was observed to induce hepatoxicity and genotoxicity, hence impairing the normal liver function and gene structure.

  17. Leflunomide for the treatment of rheumatoid arthritis in clinical practice: Incidence and severity of hepatotoxicity

    NARCIS (Netherlands)

    Van Roon, Eric N.; Jansen, Tim L.Th.A.; Houtman, Nella M.; Spoelstra, Piet; Brouwers, Jacobus R.B.J.

    2004-01-01

    Objective: Leflunomide is a novel disease modifying antirheumatic drug (DMARD). Because of reports on possible hepatotoxicity and adaptations in the recommendations for monitoring liver function during leflunomide treatment, we conducted a study to evaluate the incidence and severity of

  18. Predicting Hepatotoxicity of Drug Metabolites Via an Ensemble Approach Based on Support Vector Machine

    Science.gov (United States)

    Lu, Yin; Liu, Lili; Lu, Dong; Cai, Yudong; Zheng, Mingyue; Luo, Xiaomin; Jiang, Hualiang; Chen, Kaixian

    2017-11-20

    Drug-induced liver injury (DILI) is a major cause of drug withdrawal. The chemical properties of the drug, especially drug metabolites, play key roles in DILI. Our goal is to construct a QSAR model to predict drug hepatotoxicity based on drug metabolites. 64 hepatotoxic drug metabolites and 3,339 non-hepatotoxic drug metabolites were gathered from MDL Metabolite Database. Considering the imbalance of the dataset, we randomly split the negative samples and combined each portion with all the positive samples to construct individually balanced datasets for constructing independent classifiers. Then, we adopted an ensemble approach to make prediction based on the results of all individual classifiers and applied the minimum Redundancy Maximum Relevance (mRMR) feature selection method to select the molecular descriptors. Eventually, for the drugs in the external test set, a Bayesian inference method was used to predict the hepatotoxicity of a drug based on its metabolites. The model showed the average balanced accuracy=78.47%, sensitivity =74.17%, and specificity=82.77%. Five molecular descriptors characterizing molecular polarity, intramolecular bonding strength, and molecular frontier orbital energy were obtained. When predicting the hepatotoxicity of a drug based on all its metabolites, the sensitivity, specificity and balanced accuracy were 60.38%, 70.00%, and 65.19%, respectively, indicating that this method is useful for identifying the hepatotoxicity of drugs. We developed an in silico model to predict hepatotoxicity of drug metabolites. Moreover, Bayesian inference was applied to predict the hepatotoxicity of a drug based on its metabolites which brought out valuable high sensitivity and specificity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Risk of hepatotoxicity associated with the use of telithromycin: a signal detection using data mining algorithms.

    Science.gov (United States)

    Chen, Yan; Guo, Jeff J; Healy, Daniel P; Lin, Xiaodong; Patel, Nick C

    2008-12-01

    With the exception of case reports, limited data are available regarding the risk of hepatotoxicity associated with the use of telithromycin. To detect the safety signal regarding the reporting of hepatotoxicity associated with the use of telithromycin using 4 commonly employed data mining algorithms (DMAs). Based on the Adverse Events Reporting System (AERS) database of the Food and Drug Administration, 4 DMAs, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the information component (IC), and the Gamma Poisson Shrinker (GPS), were applied to examine the association between the reporting of hepatotoxicity and the use of telithromycin. The study period was from the first quarter of 2004 to the second quarter of 2006. The reporting of hepatotoxicity was identified using the preferred terms indexed in the Medical Dictionary for Regulatory Activities. The drug name was used to identify reports regarding the use of telithromycin. A total of 226 reports describing hepatotoxicity associated with the use of telithromycin were recorded in the AERS. A safety problem of telithromycin associated with increased reporting of hepatotoxicity was clearly detected by 4 algorithms as early as 2005, signaling the problem in the first quarter by the ROR and the IC, in the second quarter by the PRR, and in the fourth quarter by the GPS. A safety signal was indicated by the 4 DMAs suggesting an association between the reporting of hepatotoxicity and the use of telithromycin. Given the wide use of telithromycin and serious consequences of hepatotoxicity, clinicians should be cautious when selecting telithromycin for treatment of an infection. In addition, further observational studies are required to evaluate the utility of signal detection systems for early recognition of serious, life-threatening, low-frequency drug-induced adverse events.

  20. Hepatotoxicity evaluation of traditional Chinese medicines using a computational molecular model.

    Science.gov (United States)

    Zhao, Pan; Liu, Bin; Wang, Chunya

    2017-11-01

    Liver injury caused by traditional Chinese medicines (TCMs) is reported from many countries around the world. TCM hepatotoxicity has attracted worldwide concerns. This study aims to develop a more applicable and optimal tool to evaluate TCM hepatotoxicity. A quantitative structure-activity relationship (QSAR) analysis was performed based on published data and U.S. Food and Drug Administration's Liver Toxicity Knowledge Base (LTKB). Eleven herbal ingredients with proven liver toxicity in the literature were added into the dataset besides chemicals from LTKB. The finally generated QSAR model yielded a sensitivity of 83.8%, a specificity of 70.1%, and an accuracy of 80.2%. Among the externally tested 20 ingredients from TCMs, 14 hepatotoxic ingredients were all accurately identified by the QSAR model derived from the dataset containing natural hepatotoxins. Adding natural hepatotoxins into the dataset makes the QSAR model more applicable for TCM hepatotoxicity assessment, which provides a right direction in the methodology study for TCM safety evaluation. The generated QSAR model has the practical value to prioritize the hepatotoxicity risk of TCM compounds. Furthermore, an open-access international specialized database on TCM hepatotoxicity should be quickly established.

  1. Evaluation of miR-122 as a Serum Biomarker for Hepatotoxicity in Investigative Rat Toxicology Studies.

    Science.gov (United States)

    Sharapova, T; Devanarayan, V; LeRoy, B; Liguori, M J; Blomme, E; Buck, W; Maher, J

    2016-01-01

    MicroRNAs are short noncoding RNAs involved in regulation of gene expression. Certain microRNAs, including miR-122, seem to have ideal properties as biomarkers due to good stability, high tissue specificity, and ease of detection across multiple species. Recent reports have indicated that miR-122 is a highly liver-specific marker detectable in serum after liver injury. The purpose of the current study was to assess the performance of miR-122 as a serum biomarker for hepatotoxicity in short-term (5-28 days) repeat-dose rat toxicology studies when benchmarked against routine clinical chemistry and histopathology. A total of 23 studies with multiple dose levels of experimental compounds were examined, and they included animals with or without liver injury and with various hepatic histopathologic changes. Serum miR-122 levels were quantified by reverse transcription quantitative polymerase chain reaction. Increases in circulating miR-122 levels highly correlated with serum elevations of liver enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH). Statistical analysis showed that miR-122 outperformed ALT as a biomarker for histopathologically confirmed liver toxicity and was equivalent in performance to AST and GLDH. Additionally, an increase of 4% in predictive accuracy was obtained using a multiparameter approach incorporating miR-122 with ALT, AST, and GLDH. In conclusion, serum miR-122 levels can be utilized as a biomarker of hepatotoxicity in acute and subacute rat toxicology studies, and its performance can rival or exceed those of standard enzyme biomarkers such as the liver transaminases. © The Author(s) 2015.

  2. Modulatory potentials of the aqueous stem bark extract of Mangifera indica on carbon tetrachloride-induced hepatotoxicity in rats

    Science.gov (United States)

    Adeneye, Adejuwon Adewale; Awodele, Olufunsho; Aiyeola, Sheriff Aboyade; Benebo, Adokiye Senibo

    2015-01-01

    group, with more protection offered in the curative than the chemopreventive models of CCl4 hepatotoxicity. Thus, these results indicate that MIASE has a profound protective effect against acute CCl4-induced hepatotoxicity in rats, which may be due to its free radicals scavenging effect, inhibition of lipid peroxidation, and its ability to increase antioxidant activity. PMID:26151020

  3. Modulatory potentials of the aqueous stem bark extract of Mangifera indica on carbon tetrachloride-induced hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Adejuwon Adewale Adeneye

    2015-04-01

    group, with more protection offered in the curative than the chemopreventive models of CCl4 hepatotoxicity. Thus, these results indicate that MIASE has a profound protective effect against acute CCl4-induced hepatotoxicity in rats, which may be due to its free radicals scavenging effect, inhibition of lipid peroxidation, and its ability to increase antioxidant activity.

  4. Metabolomic analysis for combined hepatotoxicity of chlorpyrifos and cadmium in rats

    International Nuclear Information System (INIS)

    Xu, Ming-Yuan; Wang, Pan; Sun, Ying-Jian; Wu, Yi-Jun

    2017-01-01

    Pesticides and heavy metals are widespread environmental pollutants. Although the acute toxicity of organophosphorus pesticide chlorpyrifos (CPF) and toxic heavy metal cadmium (Cd) is well characterized, the combined toxicity of CPF and Cd, especially the hepatotoxicity of the two chemicals with long-term exposure at a low dose, remained unclear. In this study, we investigated the toxicity in the liver of rats upon subchronic exposure to CPF and Cd at environmentally relevant doses. Rats were given three different doses (1/135 LD 50 , 1/45 LD 50 and 1/15 LD 50 ) of CPF and Cd as well as their mixtures by oral gavage for 90 days. After treatment, the liver tissues were subjected to histopathological examination and biochemical analysis. Gas chromatography-mass spectrometry (GC–MS) was used to analyze the metabolomic changes in the rat liver upon CPF, Cd and their mixtures treatment. The results showed that CPF and Cd-induced oxidative damage and disrupted energy, amino acid, and fatty acid metabolism in the liver. Eleven biomarkers in liver were identified for CPF-, Cd-, and their mixture-treated rats. Three metabolites, i.e., butanedioic acid, myo-inositol, and urea, were identified as unique biomarkers for the mixture-treated rats. Moreover, we found that Cd could accelerate the metabolism of CPF in the liver when given together to the rats, which may lead to the potential antagonistic interaction between CPF and Cd. In conclusion, our results indicated that even at environmentally relevant doses, CPF and Cd could disrupt the liver metabolism. In addition, the accelerated metabolism of CPF by Cd may lead to their potential antagonistic interaction.

  5. Ipomoea aquatica Extract Shows Protective Action Against Thioacetamide-Induced Hepatotoxicity

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    A. Hamid A. Hadi

    2012-05-01

    Full Text Available In the Indian system of traditional medicine (Ayurveda it is recommended to consume Ipomoea aquatica to mitigate disorders like jaundice. In this study, the protective effects of ethanol extract of I. aquatica against liver damage were evaluated in thioacetamide (TAA-induced chronic hepatotoxicity in rats. There was no sign of toxicity in the acute toxicity study, in which Sprague-Dawley (SD rats were orally fed with I. aquatica (250 and 500 mg/kg for two months along with administration of TAA (i.p injection 200 mg/kg three times a week for two months. The results showed that the treatment of I. aquatica significantly lowered the TAA-induced serum levels of hepatic enzyme markers (ALP, ALT, AST, protein, albumin, bilirubin and prothrombin time. The hepatic content of activities and expressions SOD and CAT that were reduced by TAA were brought back to control levels by the plant extract supplement. Meanwhile, the rise in MDA level in the TAA receiving groups also were significantly reduced by I. aquatica treatment. Histopathology of hepatic tissues by H&E and Masson trichrome stains displayed that I. aquatica has reduced the incidence of liver lesions, including hepatic cells cloudy swelling, infiltration, hepatic necrosis, and fibrous connective tissue proliferation induced by TAA in rats. Therefore, the results of this study show that the protective effect of I. aquatica in TAA-induced liver damage might be contributed to its modulation on detoxification enzymes and its antioxidant and free radical scavenger effects. Moreover, it confirms a scientific basis for the traditional use of I. aquatica for the treatment of liver disorders.

  6. Can mixtures of cyanotoxins represent a risk to the zooplankton? The case study of Daphnia magna Straus exposed to hepatotoxic and neurotoxic cyanobacterial extracts.

    Science.gov (United States)

    Freitas, Emanuela Cristina; Pinheiro, Carlos; Rocha, Odete; Loureiro, Susana

    2014-01-01

    Worldwide, cyanobacterial blooms have been increasing in intensity and frequency, with toxic cyanobacteria sometimes dominant throughout the year in many freshwater bodies. Since the coexistence of more than one type of cyanotoxins in freshwater environments is a common phenomenon, studies on the joint effects of these toxins would be very useful. In this study, the single and combined effects of two cyanotoxins with different modes of action (hepatotoxic and neurotoxic) on the survival (lethal exposure) and feeding (sublethal exposure) of the cladoceran Daphnia magna were investigated. With the single exposures, it was observed that both the survival and feeding activity of the daphnids were impaired by the hepatotoxic and neurotoxic extracts at environmentally relevant concentrations. In the combined exposures, both survival and feeding rate endpoints showed a good fit to the independent action model. For the acute assay and 24h exposure period in the feeding inhibition test, there was no interaction between components of the hepatotoxic and neurotoxic extracts, although a slight tendency to a synergistic deviation could be seen in the feeding rates. On the other hand, for the 4h post-exposure period, a synergistic deviation was found in feeding rates at all mixture concentrations tested. Hence, the combined exposure of hepatotoxins and neurotoxins should also be taken into account in risk assessments of freshwater bodies, since the mixture of these toxins can result in more severe post-exposure effects on the feeding of daphnids than the sum of those expected for single exposures. Copyright © 2013 Elsevier B.V. All rights reserved.

  7. Engineered andrographolide nanosystems for smart recovery in hepatotoxic conditions

    Science.gov (United States)

    Roy, Partha; Das, Suvadra; Auddy, Runa Ghosh; Mukherjee, Arup

    2014-01-01

    Andrographolide (AG) is one of the most potent labdane diterpenoid-type free radical scavengers available from plant sources. The compound is the principal bioactive component in Andrographis paniculata leaf extracts, and is responsible for anti-inflammatory, anticancer, and immunomodulatory activity. The application of AG in therapeutics, however, is severely constrained, due to its low aqueous solubility, short biological half-life, and poor cellular permeability. Engineered nanoparticles in biodegradable polymer systems were therefore conceived as one solution to aid in further drug-like applications of AG. In this study, a cationic modified poly(lactic-co-glycolic) acid nanosystem was applied for evaluation against experimental mouse hepatotoxic conditions. Biopolymeric nanoparticles of hydrodynamic size of 229.7±17.17 nm and ζ-potential +34.4±1.87 mV facilitated marked restoration in liver functions and oxidative stress markers. Superior dissolution for bioactive AG, hepatic residence, and favorable cytokine regulation in the liver tissues are some of the factors responsible for the newer nanosystem-assisted rapid recovery. PMID:25336950

  8. Hepatotoxicity Evaluation of Aqueous Extract from Scutia buxifolia

    Directory of Open Access Journals (Sweden)

    Margareth Linde Athayde

    2013-06-01

    Full Text Available Nowadays there is an increase in the number of people taking herbals worldwide. Scutia buxifolia is used for the treatment of hypertension, but little is known about its action on liver. Thirty-two Wistar rats were divided into four groups: control and groups treated during 30 days with 100, 200 and 400 mg of lyophilized aqueous extract of S. buxifolia (SBSB/kg of body weight. This study was planned to explore hepatotoxic effect of SBSB, which was assessed by serum transaminases (ALT and AST. Thiobarbituric acid reactive substances (TBARS levels were determined in liver, along with thiols content (NPSH, catalase (CAT activity and, superoxide dismutase (SOD enzymes. Histopathological studies of liver tissue were performed. Flavonoids and phenolics were quantified in SBSB by high performance liquid chromatography with diode array detection (HPLC/DAD. We did not observe alterations on redox status (TBARS, NPSH, CAT and, SOD in the control and experimental groups. An increase on AST activity was only observed at 200 mg of SBSB, whereas ALT score was not affected by SBSB. Moreover, no morphological alterations were observed on the hepatocytes, matching the analysed biochemical parameters. This way, we conclude that SBSB was not toxic.

  9. Analysis of 90 cases of antithyroid drug-induced severe hepatotoxicity over 13 years in China.

    Science.gov (United States)

    Yang, Jun; Li, Lin-Fa; Xu, Qin; Zhang, Jun; Weng, Wan-Wen; Zhu, Yang-Jun; Dong, Meng-Jie

    2015-03-01

    Antithyroid drug (ATD)-induced severe hepatotoxicity is a rare but serious complication of ATD therapy. The characteristics of severe hepatotoxicity have been reported in only a small number of patients. Ninety patients with ATD-induced severe hepatotoxicity presenting during a 13 year period (2000-2013) who were about to undergo nuclear medicine therapy with (131)I from a sample of 8864 patients with hyperthyroidism were studied, and the outcomes were evaluated. The mean age of the patients with ATD-induced severe hepatotoxicity was 41.6±12.5 years (mean±standard deviation), and the female to male ratio was 2.2:1. The methimazole (MMI) dose given at the onset was 19.1±7.4 mg/day. The propylthiouracil (PTU) dose given at the onset was 212.8±105.0 mg/day. ATD-induced severe hepatotoxicity occurred in 63.3%, 75.6%, and 81.1% of patients within 4, 8, and 12 weeks of the onset of ATD therapy, respectively. The types of severe hepatotoxicity did not differ significantly between the MMI and PTU groups (p=0.188). The frequency of the cholestatic type in the MMI group (35.3%, 18/51) was higher than that in the PTU group (17.9%, 7/39), but these frequencies were not significantly different (p=0.069). The patients who were treated with (131)I received an average dose of 279.1±86.1 MBq (n=84). Therapy was successful in 60 of the 67 patients (89.6%). The success rate was equivalent (p=0.696) between the groups receiving MMI (91.7%, 33/36) and PTU (87.1%, 27/31). Severe hepatotoxicity tends to occur within the first three months after the onset of ATD therapy. The type of ATD-induced severe hepatotoxicity did not differ between the MMI and PTU groups. (131)I therapy is an effective treatment approach for patients with ATD-induced severe hepatotoxicity.

  10. Toxicogenomic analysis identifies the apoptotic pathway as the main cause of hepatotoxicity induced by tributyltin.

    Science.gov (United States)

    Zhou, Mi; Feng, Mei; Fu, Ling-Ling; Ji, Lin-Dan; Zhao, Jin-Shun; Xu, Jin

    2016-11-01

    Tributyltin (TBT) is one of the most widely used organotin biocides, which has severe endocrine-disrupting effects on marine species and mammals. Given that TBT accumulates at higher levels in the liver than in any other organ, and it acts mainly as a hepatotoxic agent, it is important to clearly delineate the hepatotoxicity of TBT. However, most of the available studies on TBT have focused on observations at the cellular level, while studies at the level of genes and proteins are limited; therefore, the molecular mechanisms of TBT-induced hepatotoxicity remains largely unclear. In the present study, we applied a toxicogenomic approach to investigate the effects of TBT on gene expression in the human normal liver cell line HL7702. Gene expression profiling identified the apoptotic pathway as the major cause of hepatotoxicity induced by TBT. Flow cytometry assays confirmed that medium- and high-dose TBT treatments significantly increased the number of apoptotic cells, and more cells underwent late apoptosis in the high-dose TBT group. The genes encoding heat shock proteins (HSPs), kinases and tumor necrosis factor receptors mediated TBT-induced apoptosis. These findings revealed novel molecular mechanisms of TBT-induced hepatotoxicity, and the current microarray data may also provide clues for future studies. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Modeling drug- and chemical- induced hepatotoxicity with systems biology approaches

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    Sudin eBhattacharya

    2012-12-01

    Full Text Available We provide an overview of computational systems biology approaches as applied to the study of chemical- and drug-induced toxicity. The concept of ‘toxicity pathways’ is described in the context of the 2007 US National Academies of Science report, Toxicity testing in the 21st Century: A Vision and A Strategy. Pathway mapping and modeling based on network biology concepts are a key component of the vision laid out in this report for a more biologically-based analysis of dose-response behavior and the safety of chemicals and drugs. We focus on toxicity of the liver (hepatotoxicity – a complex phenotypic response with contributions from a number of different cell types and biological processes. We describe three case studies of complementary multi-scale computational modeling approaches to understand perturbation of toxicity pathways in the human liver as a result of exposure to environmental contaminants and specific drugs. One approach involves development of a spatial, multicellular virtual tissue model of the liver lobule that combines molecular circuits in individual hepatocytes with cell-cell interactions and blood-mediated transport of toxicants through hepatic sinusoids, to enable quantitative, mechanistic prediction of hepatic dose-response for activation of the AhR toxicity pathway. Simultaneously, methods are being developing to extract quantitative maps of intracellular signaling and transcriptional regulatory networks perturbed by environmental contaminants, using a combination of gene expression and genome-wide protein-DNA interaction data. A predictive physiological model (DILIsymTM to understand drug-induced liver injury (DILI, the most common adverse event leading to termination of clinical development programs and regulatory actions on drugs, is also described. The model initially focuses on reactive metabolite-induced DILI in response to administration of acetaminophen, and spans multiple biological scales.

  12. Evaluation of an in vitro toxicogenetic mouse model for hepatotoxicity

    International Nuclear Information System (INIS)

    Martinez, Stephanie M.; Bradford, Blair U.; Soldatow, Valerie Y.; Kosyk, Oksana; Sandot, Amelia; Witek, Rafal; Kaiser, Robert; Stewart, Todd; Amaral, Kirsten; Freeman, Kimberly; Black, Chris; LeCluyse, Edward L.; Ferguson, Stephen S.; Rusyn, Ivan

    2010-01-01

    Numerous studies support the fact that a genetically diverse mouse population may be useful as an animal model to understand and predict toxicity in humans. We hypothesized that cultures of hepatocytes obtained from a large panel of inbred mouse strains can produce data indicative of inter-individual differences in in vivo responses to hepato-toxicants. In order to test this hypothesis and establish whether in vitro studies using cultured hepatocytes from genetically distinct mouse strains are feasible, we aimed to determine whether viable cells may be isolated from different mouse inbred strains, evaluate the reproducibility of cell yield, viability and functionality over subsequent isolations, and assess the utility of the model for toxicity screening. Hepatocytes were isolated from 15 strains of mice (A/J, B6C3F1, BALB/cJ, C3H/HeJ, C57BL/6J, CAST/EiJ, DBA/2J, FVB/NJ, BALB/cByJ, AKR/J, MRL/MpJ, NOD/LtJ, NZW/LacJ, PWD/PhJ and WSB/EiJ males) and cultured for up to 7 days in traditional 2-dimensional culture. Cells from B6C3F1, C57BL/6J, and NOD/LtJ strains were treated with acetaminophen, WY-14,643 or rifampin and concentration-response effects on viability and function were established. Our data suggest that high yield and viability can be achieved across a panel of strains. Cell function and expression of key liver-specific genes of hepatocytes isolated from different strains and cultured under standardized conditions are comparable. Strain-specific responses to toxicant exposure have been observed in cultured hepatocytes and these experiments open new opportunities for further developments of in vitro models of hepatotoxicity in a genetically diverse population.

  13. The hepatotoxicity of multi-walled carbon nanotubes in mice

    Science.gov (United States)

    Ji, Zongfei; Zhang, Danying; Li, Ling; Shen, Xizhong; Deng, Xiaoyong; Dong, Ling; Wu, Minhong; Liu, Yuanfang

    2009-11-01

    The hepatotoxicity of two types of multi-walled carbon nanotubes (MWCNTs), acid-oxidized MWCNTs (O-MWCNTs) and Tween-80-dispersed MWCNTs (T-MWCNTs), were investigated with Kunming mice exposed to 10 and 60 mg kg-1 by intravenous injection for 15 and 60 d. Compared with the PBS group, the body-weight gain of the mice decreased and the level of total bilirubin and aspartate aminotransferase increased in the MWCNT-exposed group with a significant dose-effect relationship, while tumor necrosis factor alpha level did not show significant statistical change within 60 d. Spotty necrosis, inflammatory cell infiltration in portal region, hepatocyte mitochondria swelling and lysis were observed with a significant dose-effect relationship in the MWCNT groups. Liver damage of the T-MWCNT group was more severe than that of the O-MWCNT group according to the Roenigk classification system. Furthermore, T-MWCNTs induce slight liver oxidative damage in mice at 15 d, which was recovered at 60 d. Part of the gene expressions of mouse liver in the MWCNT groups changed compared to the PBS group, including GPCRs (G protein-coupled receptors), cholesterol biosynthesis, metabolism by cytochrome P450, natural-killer-cell-mediated cytotoxicity, TNF- α, NF-κB signaling pathway, etc. In the P450 pathway, the gene expressions of Gsta2 (down-regulated), Cyp2B19 (up-regulated) and Cyp2C50 (down-regulated) had significant changes in the MWCNT groups. These results show that a high dose of T-MWCNTs can induce hepatic toxicity in mice while O-MWCNTs seem to have less toxicity.

  14. Acute bile nephropathy secondary to anabolic steroids.

    Science.gov (United States)

    Alkhunaizi, Ahmed M; ElTigani, Mohamed A; Rabah, Rola S; Nasr, Samih H

    2016-02-01

    Renal dysfunction in cholestatic liver disease is multifactorial. Acute kidney injury may develop secondary to renal vasoconstriction in the setting of peripheral vasodilation and relative hypovolemia, tubular obstruction by bile casts, and direct tubular toxicity from bile. Anabolic steroids are frequently used by athletes to boost endurance and increase muscle mass. These agents are a recently recognized cause of hepatotoxicity and jaundice and may lead to acute kidney injury. To increase awareness about this growing problem and to characterize the pathology of acute kidney injury in this setting, we report on a young male who developed acute kidney injury in the setting of severe cholestatic jaundice related to ingestion of anabolic steroids used for bodybuilding. Kidney biopsy showed bile casts within distal tubular lumina, filamentous bile inclusions within tubular cells, and signs of acute tubular injury. This report supports the recently re-emerged concept of bile nephropathy cholemic nephrosis.

  15. Gastric emptying in rats with acetaminophen-induced hepatitis

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    G. Hessel

    1998-09-01

    Full Text Available The objective of this work was to study the gastric emptying (GE of liquids in fasted and sucrose-fed rats with toxic hepatitis induced by acetaminophen. The GE of three test meals (saline, glucose and mayonnaise was evaluated in Wistar rats. For each meal, the animals were divided into two groups (N = 24 each. Group I was fed a sucrose diet throughout the experiment (66 h while group II was fasted. Forty-two hours after the start of the experiment, each group was divided into two subgroups (N = 12 each. Subgroup A received a placebo and subgroup B was given acetaminophen (1 g/kg. Twenty-four hours later, the GE of the three test meals was assessed and blood samples were collected to measure the serum levels of alanine aminotransferase (ALT, aspartate aminotransferase (AST and acetaminophen. In group IB, the mean AST and ALT values were 515 and 263 IU/l, respectively, while for group IIB they were 4014 and 2472 IU/l, respectively. The mean serum acetaminophen levels were higher in group IIB (120 µg/ml than in group IB (87 µg/ml. The gastric retention values were significantly higher in group IIB than in group IIA for all three test meals: saline, 51 vs 35%; glucose, 52 vs 38% and mayonnaise, 51 vs 29% (median values. The correlation between gastric retention and AST levels was significant (P<0.05 for group IIB for the three test meals: r = 0.73, 0.67 and 0.68 for saline, glucose and mayonnaise, respectively. We conclude that GE is altered in rats with hepatic lesions induced by acetaminophen, and that these alterations may be related to the liver cell necrosis caused by the drug.

  16. STUDIES ON INDUCED HEPATOTOXICITY IN MALE ALBINO RATS (RATTUS NORVEGICUS)

    International Nuclear Information System (INIS)

    ABULYAZID, I.; ABBAS, O.A.; FAYEZ, V.

    2008-01-01

    Levanox, a hepato protective drug, and garlic powder have been considered as safe anti-oxidant agents. The present investigation refers to biochemical and molecular studies to evaluate the protective role of levanox and/or garlic powder toward CCl4-induced toxicity in adult male albino rats. CCl4 intoxication was attempted using a dose of 0.03 ml/kg of rat body weight.Pre-treatment with levanox (one capsule/ kg of rat body weight, each capsule contains 100 mg catechu, 7.5 mg dandelion, 75 mg termiric 2 % curcumin , 17.5 mg silymarin, 100 mg lecithin) was more effective than garlic powder (100mg/kg of rat body weight) in reducing CCl4-induced hepatotoxicity as revealed by its higher potency in reducing elevation of aspartate (AST) and alanine (ALT) aminotransferases in serum. Serum of control rats and those treated with levanox or garlic or CCl4 produced 13 types of proteins, differing in the molecular weight (MW) and densities, while those of levanox + garlic or garlic +CCl4 produced 14 bands differing in the MW and densities. The similarity index at the epigenetic level was also studied using the primers under study. The control sample produced one amplified DNA fragment with Rf of 0.73 and a molecular size (MS) of 67 base pair (bp) . Using the same primers, no amplified DNA fragment with the same MS was produced in the sample taken from levanox + garlic treated group.OPA-2 primer of sequence 5?- AGA TGC AGC C-3? produced one amplified DNA band with MS of 292 bp and Rf of 0.46 . However, the same primer produced one amplified DNA characteristic band with a molecular size of 363 bp and Rf of 0.43 in the sample of levanox + garlic group.In the control sample, OPA-4 primer of sequence 5? - ACG CAC AAC C-3? produced one amplified DNA band of MS of 299 bp and Rf of 0.43. The same primer produced one amplified characteristic DNA band with MS of 363 bp and Rf of 0.43 in the sample of levanox + garlic group.Dual treatment with levanox and garlic powder resulted in a

  17. Infliximab Modulates Cisplatin-Induced Hepatotoxicity in Rats

    Directory of Open Access Journals (Sweden)

    Medine Cumhur Cüre

    2016-10-01

    Full Text Available Background: Cisplatin (Cis is one of the most commonly used antineoplastic drugs. It is used as chemotherapy for many solid organ malignancies such as brain, neck, male and female urogenital, vesical and pulmonary cancers. Infliximab blocks tumor necrosis factor alpha (TNF-α. Several studies have reported that infliximab ameliorates cell damage by reducing cytokine levels. Aims: We aimed to investigate whether infliximab has a preventive effect against cisplatin-induced hepatotoxicity and whether it has a synergistic effect when combined with Cis. Study Design: Animal experimentation. Methods: Male Wistar albino rats were divided in three groups as follows: Cis group, infliximab + Cis (CIN group and the control group. Each group comprised 10 animals. Animals in the Cis group received an intraperitoneal single-dose injection of Cis (7 mg/kg. In the CIN group, a single dose of infliximab (7 mg/kg was administered 72 h prior to the Cis injection. After 72 h, a single dose of Cis (7 mg/kg was administered. All rats were sacrificed five days after Cis injection. Results: TNF-α levels in the Cis group were significantly higher (345.5±40.0 pg/mg protein than those of the control (278.7±62.1 pg/mg protein, p=0.003 and CIN groups (239.0±64.2 pg/mg protein, p=0.013. The Cis group was found to have high carbonic anhydrase (CA-II and low carbamoyl phosphate synthetase-1 (CPS-1 levels. Aspartate transaminase (AST and alanine transaminase (ALT levels were lower in the CIN group as compared to the Cis group. Total histological damage was greater in the Cis group as compared to the control and CIN groups. Conclusion: Cis may lead to liver damage by increasing cytokine levels. It may increase oxidative stress-induced tissue damage by increasing carbonic anhydrase II (CA-II enzyme levels and decreasing CPS-1 enzyme levels. Infliximab decreases Cis-induced hepatic damage by blocking TNF-α and it may also protect against liver damage by regulating CPS-1 and

  18. Evaluation of the zebrafish embryo as an alternative model for hepatotoxicity testing

    NARCIS (Netherlands)

    Driessen, Marja

    2014-01-01

    In this thesis we showed the applicability of the zebrafish embryo as an alternative model for hepatotoxicity testing using analysis of mechanisms through toxicogenomics. By applying a variety of toxicogenomics techniques, we were able to characterize specific responses. NGS revealed that

  19. Protective effect of rutin in comparison to silymarin against induced hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    M. Kasi Reddy

    2017-01-01

    Full Text Available Aim: The aim of this study is to evaluate the hepatoprotective effect of rutin (RTN in comparison to silymarin (SLM against acetaminophen (APAP-induced hepatotoxicity in rats. Materials and Methods: Male Wistar albino rats (n=24 of 3 months age were equally divided into four groups. Group 1 served as normal control. Hepatotoxicity was induced in the remaining three groups with administration of 500 mg/kg po APAP from day 1-3. Groups 2, 3, and 4 were subsequently administered orally with distilled water, 25 mg/kg of SLM, and 20 mg/kg of RTN, respectively, for 11 days. The mean body weights and biomarkers of hepatotoxicity were estimated on day 0, 4 (confirmation of toxicity, and 15 (at the end of treatment. Hematological parameters were evaluated on day 4 and 15. Antioxidant profile and adenosine triphosphatases (ATPases were assessed at the end of the experiment. Liver tissues were subjected to histopathology and transmission electron microscopy after the sacrifice on day 15. Results: Antioxidant profile, ATPases, and hematological and sero-biochemical parameters were significantly altered, and histopathological changes were noticed in the liver of toxic control group. These changes were reversed in groups 3 and 4 that were administered with SLM and RTN, respectively. Conclusion: The results of the present investigation enunciated that SLM has potent hepatoprotective activity though the RTN was found superior in restoring the pathological alterations in paracetamol-induced hepatotoxicity in Wistar albino rats.

  20. Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro

    NARCIS (Netherlands)

    Hof, Van den W.F.P.M.; Ruiz Aracama, Ainhoa; Summeren, Van Anke; Jennen, D.G.J.; Gaj, Stan; Coonen, M.L.J.; Brauers, Karen; Wodzig, W.K.W.H.; Delft, van J.H.M.; Kleinjans, J.C.S.

    2015-01-01

    In order to improve attrition rates of candidate-drugs there is a need for a better understanding of the mechanisms underlying drug-induced hepatotoxicity. We aim to further unravel the toxicological response of hepatocytes to a prototypical cholestatic compound by integrating transcriptomic and

  1. Hepatotoxic effects of fenofibrate in spontaneously hypertensive rats expressing human C-reactive protein

    Czech Academy of Sciences Publication Activity Database

    Škop, V.; Trnovská, J.; Oliyarnyk, O.; Marková, I.; Malínská, H.; Kazdová, L.; Zídek, Václav; Landa, Vladimír; Mlejnek, Petr; Šimáková, Miroslava; Kůdela, M.; Pravenec, Michal; Šilhavý, Jan

    2016-01-01

    Roč. 65, č. 6 (2016), s. 891-899 ISSN 0862-8408 R&D Projects: GA MZd(CZ) NT14325 Institutional support: RVO:67985823 Keywords : fenofibrate * rosuvastatin * C-reactive protein * transgenic * spontaneously hypertensive rat * inflammation * hepatotoxic Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 1.461, year: 2016

  2. Advancing Predictive Hepatotoxicity at the Intersection of Experimental, in Silico, and Artificial Intelligence Technologies.

    Science.gov (United States)

    Fraser, Keith; Bruckner, Dylan M; Dordick, Jonathan S

    2018-06-18

    Adverse drug reactions, particularly those that result in drug-induced liver injury (DILI), are a major cause of drug failure in clinical trials and drug withdrawals. Hepatotoxicity-mediated drug attrition occurs despite substantial investments of time and money in developing cellular assays, animal models, and computational models to predict its occurrence in humans. Underperformance in predicting hepatotoxicity associated with drugs and drug candidates has been attributed to existing gaps in our understanding of the mechanisms involved in driving hepatic injury after these compounds perfuse and are metabolized by the liver. Herein we assess in vitro, in vivo (animal), and in silico strategies used to develop predictive DILI models. We address the effectiveness of several two- and three-dimensional in vitro cellular methods that are frequently employed in hepatotoxicity screens and how they can be used to predict DILI in humans. We also explore how humanized animal models can recapitulate human drug metabolic profiles and associated liver injury. Finally, we highlight the maturation of computational methods for predicting hepatotoxicity, the untapped potential of artificial intelligence for improving in silico DILI screens, and how knowledge acquired from these predictions can shape the refinement of experimental methods.

  3. Anti-tuberculosis therapy-induced hepatotoxicity among Ethiopian HIV-positive and negative patients.

    Directory of Open Access Journals (Sweden)

    Getnet Yimer

    2008-03-01

    Full Text Available To assess and compare the prevalence, severity and prognosis of anti-TB drug induced hepatotoxicity (DIH in HIV positive and HIV negative tuberculosis (TB patients in Ethiopia.In this study, 103 HIV positive and 94 HIV negative TB patients were enrolled. All patients were evaluated for different risk factors and monitored biochemically and clinically for development of DIH. Sub-clinical hepatotoxicity was observed in 17.3% of the patients and 8 out of the 197 (4.1% developed clinical hepatotoxicity. Seven of the 8 were HIV positive and 2 were positive for HBsAg.Sub-clinical hepatotoxicity was significantly associated with HIV co-infection (p = 0.002, concomitant drug intake (p = 0.008, and decrease in CD4 count (p = 0.001. Stepwise restarting of anti TB treatment was also successful in almost all the patients who developed clinical DIH. We therefore conclude that anti-TB DIH is a major problem in HIV-associated TB with a decline in immune status and that there is a need for a regular biochemical and clinical follow up for those patients who are at risk.

  4. Enhancement of the predicted drug hepatotoxicity in gel entrapped hepatocytes within polysulfone-g-poly (ethylene glycol) modified hollow fiber

    International Nuclear Information System (INIS)

    Shen Chong; Zhang Guoliang; Meng Qin

    2010-01-01

    Collagen gel-based 3D cultures of hepatocytes have been proposed for evaluation of drug hepatotoxicity because of their more reliability than traditional monolayer culture. The collagen gel entrapment of hepatocytes in hollow fibers has been proven to well reflect the drug hepatotoxicity in vivo but was limited by adsorption of hydrophobic drugs onto hollow fibers. This study aimed to investigate the impact of hollow fibers on hepatocyte performance and drug hepatotoxicity. Polysulfone-g-poly (ethylene glycol) (PSf-g-PEG) hollow fiber was fabricated and applied for the first time to suppress the drug adsorption. Then, the impact of hollow fibers was evaluated by detecting the hepatotoxicity of eight selected drugs to gel entrapped hepatocytes within PSf and PSf-g-PEG hollow fibers, or without hollow fibers. The hepatocytes in PSf-g-PEG hollow fiber showed the highest sensitivity to drug hepatotoxicity, while those in PSf hollow fiber and cylindrical gel without hollow fiber underestimated the hepatotoxicity due to either drug adsorption or low hepatic functions. Therefore, the 3D culture of gel entrapped hepatocytes within PSf-g-PEG hollow fiber would be a promising tool for investigation of drug hepatotoxicity in vitro.

  5. Herbal hepatotoxicity in traditional and modern medicine: actual key issues and new encouraging steps

    Science.gov (United States)

    Teschke, Rolf; Eickhoff, Axel

    2015-01-01

    Plants are natural producers of chemical substances, providing potential treatment of human ailments since ancient times. Some herbal chemicals in medicinal plants of traditional and modern medicine carry the risk of herb induced liver injury (HILI) with a severe or potentially lethal clinical course, and the requirement of a liver transplant. Discontinuation of herbal use is mandatory in time when HILI is first suspected as diagnosis. Although, herbal hepatotoxicity is of utmost clinical and regulatory importance, lack of a stringent causality assessment remains a major issue for patients with suspected HILI, while this problem is best overcome by the use of the hepatotoxicity specific CIOMS (Council for International Organizations of Medical Sciences) scale and the evaluation of unintentional reexposure test results. Sixty five different commonly used herbs, herbal drugs, and herbal supplements and 111 different herbs or herbal mixtures of the traditional Chinese medicine (TCM) are reported causative for liver disease, with levels of causality proof that appear rarely conclusive. Encouraging steps in the field of herbal hepatotoxicity focus on introducing analytical methods that identify cases of intrinsic hepatotoxicity caused by pyrrolizidine alkaloids, and on omics technologies, including genomics, proteomics, metabolomics, and assessing circulating micro-RNA in the serum of some patients with intrinsic hepatotoxicity. It remains to be established whether these new technologies can identify idiosyncratic HILI cases. To enhance its globalization, herbal medicine should universally be marketed as herbal drugs under strict regulatory surveillance in analogy to regulatory approved chemical drugs, proving a positive risk/benefit profile by enforcing evidence based clinical trials and excellent herbal drug quality. PMID:25954198

  6. Herbal hepatotoxicity in traditional and modern medicine: actual key issues and new encouraging steps.

    Science.gov (United States)

    Teschke, Rolf; Eickhoff, Axel

    2015-01-01

    Plants are natural producers of chemical substances, providing potential treatment of human ailments since ancient times. Some herbal chemicals in medicinal plants of traditional and modern medicine carry the risk of herb induced liver injury (HILI) with a severe or potentially lethal clinical course, and the requirement of a liver transplant. Discontinuation of herbal use is mandatory in time when HILI is first suspected as diagnosis. Although, herbal hepatotoxicity is of utmost clinical and regulatory importance, lack of a stringent causality assessment remains a major issue for patients with suspected HILI, while this problem is best overcome by the use of the hepatotoxicity specific CIOMS (Council for International Organizations of Medical Sciences) scale and the evaluation of unintentional reexposure test results. Sixty five different commonly used herbs, herbal drugs, and herbal supplements and 111 different herbs or herbal mixtures of the traditional Chinese medicine (TCM) are reported causative for liver disease, with levels of causality proof that appear rarely conclusive. Encouraging steps in the field of herbal hepatotoxicity focus on introducing analytical methods that identify cases of intrinsic hepatotoxicity caused by pyrrolizidine alkaloids, and on omics technologies, including genomics, proteomics, metabolomics, and assessing circulating micro-RNA in the serum of some patients with intrinsic hepatotoxicity. It remains to be established whether these new technologies can identify idiosyncratic HILI cases. To enhance its globalization, herbal medicine should universally be marketed as herbal drugs under strict regulatory surveillance in analogy to regulatory approved chemical drugs, proving a positive risk/benefit profile by enforcing evidence based clinical trials and excellent herbal drug quality.

  7. Hepatotoxicity in HIV-infected children and adolescents on antiretroviral therapy

    Directory of Open Access Journals (Sweden)

    Ana Cecília Montes Gil

    Full Text Available CONTEXT AND OBJECTIVE: Adverse drug reactions are a significant problem in patients on antiretroviral therapy (ART. We determined liver enzyme elevation frequencies in HIV-infected children and adolescents receiving ART, and their association with risk factors. DESIGN AND SETTING: Cross-sectional study, at the Pediatrics Immunodeficiency Division, University Hospital, Universidade Estadual de Campinas. METHODS: Medical records of 152 children and adolescents (54.6% male; median age 7.48 years were analyzed, with a mean of 2.6 liver enzyme determinations per patient. Clinically, patients were classified in categories N (6, A (29, B (78 and C (39. Serum levels of aspartate aminotransferase and alanine aminotransferase were evaluated. Hepatotoxicity was scored as grade 1 (1.1-4.9 times upper limit of normality, ULN, grade 2 (5.0-9.9 times ULN, grade 3 (10.0-15.0 times ULN and grade 4 (> 15.0 times ULN. To assess hepatotoxicity risk factors, odds ratios (OR and adjusted odds ratios (aOR for age, gender, TCD4+ cell count, viral load and medication usage were calculated. RESULTS: We observed grade 1 hepatotoxicity in 19.7 % (30/152 patients. No cases of grade 2, 3 or 4 were detected. There was a significant association between hepatotoxicity and use of sulfonamides (OR, 3.61; 95% confidence interval (CI, 1.50-8.70; aOR, 3.58; 95% CI, 1.44-8.85 and antituberculous agents (OR, 9.23; 95% CI, 1.60-53.08; aOR, 9.05; 95% CI, 1.48-55.25. No toxicity was associated with ART. CONCLUSIONS: One fifth of patients experienced mild hepatotoxicity, attributed to antituberculous agents and sulfonamides. Our results suggest that ART was well tolerated.

  8. Herbal hepatotoxicity in traditional and modern medicine: Actual key issues and new encouraging steps

    Directory of Open Access Journals (Sweden)

    Rolf eTeschke

    2015-04-01

    Full Text Available Plants are natural producers of chemical substances, providing potential treatment of human ailments since ancient times. Some herbal chemicals in medicinal plants of traditional and modern medicine carry the risk of herb induced liver injury (HILI with a severe or potentially lethal clinical course, and the requirement of a liver transplant. Discontinuation of herbal use is mandatory in time when HILI is first suspected as diagnosis. Although herbal hepatotoxicity is of utmost clinical and regulatory importance, lack of a stringent causality assessment remains a major issue for patients with suspected HILI, while this problem is best overcome by the use of the hepatotoxicity specific CIOMS (Council for International Organizations of Medical Sciences scale and the evaluation of unintentional reexposure test results. Sixty five different commonly used herbs, herbal drugs, and herbal supplements and 111 different herbs or herbal mixtures of the traditional Chinese medicine (TCM are reported causative for liver disease, with levels of causality proof that appear rarely conclusive. Encouraging steps in the field of herbal hepatotoxicity focus on introducing analytical methods that identify cases of intrinsic hepatotoxicity caused by pyrrolizidine alkaloids, and on omics technologies, including genomics, proteomics, metabolomics, and assessing circulating micro-RNA in the serum of some patients with intrinsic hepatotoxicity. It remains to be established whether these new technologies can identify idiosyncratic HILI cases. To enhance its globalization, herbal medicine should universally be marketed as herbal drugs under strict regulatory surveillance in analogy to regulatory approved chemical drugs, proving a positive risk/benefit profile by enforcing evidence based clinical trials and excellent herbal drug quality.

  9. Risk assessment of hepatotoxicity among tuberculosis and human immunodeficiency virus/AIDS-coinfected patients under tuberculosis treatment

    OpenAIRE

    Williams Ngouleun; Prosper Cabral Biapa Nya; Anatole Constant Pieme; Phelix Bruno Telefo

    2016-01-01

    Objective/background: Tuberculosis (TB) is a worldwide public health problem. It is a contagious and grave disease caused by Mycobacterium tuberculosis. Current drugs such as isoniazid, pyrazinamide, and rifampicin used for the treatment of tuberculosis are potentially hepatotoxic and can lead to drug hepatitis. In order to improve the follow-up of TB patients in Cameroon, we carried out a study which aimed to evaluate the hepatotoxicity risk factors associated with anti-TB drugs. Methods:...

  10. Protective effect of the edible brown alga Ecklonia stolonifera on doxorubicin-induced hepatotoxicity in primary rat hepatocytes.

    Science.gov (United States)

    Jung, Hyun Ah; Kim, Jae-I; Choung, Se Young; Choi, Jae Sue

    2014-08-01

    As part of our efforts to isolate anti-hepatotoxic agents from marine natural products, we screened the ability of 14 edible varieties of Korean seaweed to protect against doxorubicin-induced hepatotoxicity in primary rat hepatocytes. Among the crude extracts of two Chlorophyta (Codium fragile and Capsosiphon fulvescens), seven Phaeophyta (Undaria pinnatifida, Sargassum thunbergii, Pelvetia siliquosa, Ishige okamurae, Ecklonia cava, Ecklonia stolonifera and Eisenia bicyclis), five Rhodophyta (Chondrus ocellatus, Gelidium amansii, Gracilaria verrucosa, Symphycladia latiuscula and Porphyra tenera), and the extracts of Ecklonia stolonifera, Ecklonia cava, Eisenia bicyclis and Pelvetia siliquosa exhibited significant protective effects on doxorubicin-induced hepatotoxicity, with half maximal effective concentration (EC50) values of 2.0, 2.5, 3.0 and 15.0 μg/ml, respectively. Since Ecklonia stolonifera exhibits a significant protective potential and is frequently used as foodstuff, we isolated six phlorotannins, including phloroglucinol (1), dioxinodehydroeckol (2), eckol (3), phlorofucofuroeckol A (4), dieckol (5) and triphloroethol-A (6). Phlorotannins 2 ∼ 6 exhibited potential protective effects on doxorubicin-induced hepatotoxicity, with corresponding EC50 values of 3.4, 8.3, 4.4, 5.5 and 11.5 μg/ml, respectively. The results clearly demonstrated that the anti-hepatotoxic effects of Ecklonia stolonifera and its isolated phlorotannins are useful for further exploration and development of therapeutic modalities for treatment of hepatotoxicity. © 2014 Royal Pharmaceutical Society.

  11. To Set Up a Logistic Regression Prediction Model for Hepatotoxicity of Chinese Herbal Medicines Based on Traditional Chinese Medicine Theory

    Science.gov (United States)

    Liu, Hongjie; Li, Tianhao; Zhan, Sha; Pan, Meilan; Ma, Zhiguo; Li, Chenghua

    2016-01-01

    Aims. To establish a logistic regression (LR) prediction model for hepatotoxicity of Chinese herbal medicines (HMs) based on traditional Chinese medicine (TCM) theory and to provide a statistical basis for predicting hepatotoxicity of HMs. Methods. The correlations of hepatotoxic and nonhepatotoxic Chinese HMs with four properties, five flavors, and channel tropism were analyzed with chi-square test for two-way unordered categorical data. LR prediction model was established and the accuracy of the prediction by this model was evaluated. Results. The hepatotoxic and nonhepatotoxic Chinese HMs were related with four properties (p 0.05). There were totally 12 variables from four properties and five flavors for the LR. Four variables, warm and neutral of the four properties and pungent and salty of five flavors, were selected to establish the LR prediction model, with the cutoff value being 0.204. Conclusions. Warm and neutral of the four properties and pungent and salty of five flavors were the variables to affect the hepatotoxicity. Based on such results, the established LR prediction model had some predictive power for hepatotoxicity of Chinese HMs. PMID:27656240

  12. Hepatotoxicity associated with illicit use of anabolic androgenic steroids in doping.

    Science.gov (United States)

    Solimini, R; Rotolo, M C; Mastrobattista, L; Mortali, C; Minutillo, A; Pichini, S; Pacifici, R; Palmi, I

    2017-03-01

    Anabolic Androgenic Steroids (AAS) abuse and misuse is nowadays a harmful habit involving both professional or recreational athletes, as well as general population. AAS are also frequently present in over-the-counter dietary supplements without being declared in the list of ingredients, leaving consumers unaware of the risks of adverse effects. Indeed, health risks of AAS consumption in pharmaceutical preparations or dietary complements seem still underestimated and under-reported. The variety of complications due to AAS misuse involves cardiovascular, central nervous, musculoskeletal and genitourinary systems of both males and females; psychiatric and behavioral effects, damages to metabolic system, skin and mainly liver. For instance, relevant concern has been raised by the AAS hepatotoxicity including adenoma, hepatocellular carcinoma, cholestasis, and peliosis hepatis. The present review reports the information available on the hepatotoxic effects of AAS use in professional and amateur athletes.

  13. Hibiscus vitifolius (Linn.) root extracts shows potent protective action against anti-tubercular drug induced hepatotoxicity.

    Science.gov (United States)

    Samuel, Anbu Jeba Sunilson John; Mohan, Syam; Chellappan, Dinesh Kumar; Kalusalingam, Anandarajagopal; Ariamuthu, Saraswathi

    2012-05-07

    The roots of Hibiscus vitifolius Linn. (Malvaceae) is used for the treatment of jaundice in the folklore system of medicine in India. This study is an attempt to evaluate the hepatoprotective activity of the roots of Hibiscus vitifolius against anti-tubercular drug induced hepatotoxicity. Hepatotoxicity was induced in albino rats of either sex by oral administration of a combination of three anti-tubercular drugs. Petroleum ether, chloroform, methanol and aqueous extracts of roots of Hibiscus vitifolius (400mg/kg/day) were evaluated for their possible hepatoprotective potential. All the extracts were found to be safe up to a dose of 2000mg/kg. Among the four extracts studied, oral administration of methanol extract of Hibiscus vitifolius at 400mg/kg showed significant difference in all the parameters when compared to control. There was a significant (PHibiscus vitifolius have potent hepatoprotective activity, thereby justifying its ethnopharmacological claim. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  14. Scientific and Regulatory Perspectives in Herbal and Dietary Supplement Associated Hepatotoxicity in the United States

    Directory of Open Access Journals (Sweden)

    Mark I. Avigan

    2016-03-01

    Full Text Available In the United States (US, the risk of hepatotoxicity linked to the widespread use of certain herbal products has gained increased attention among regulatory scientists. Based on current US law, all dietary supplements sold domestically, including botanical supplements, are regulated by the Food and Drug Administration (FDA as a special category of foods. Under this designation, regulatory scientists do not routinely evaluate the efficacy of these products prior to their marketing, despite the content variability and phytochemical complexity that often characterizes them. Nonetheless, there has been notable progress in the development of advanced scientific methods to qualitatively and quantitatively measure ingredients and screen for contaminants and adulterants in botanical products when hepatotoxicity is recognized.

  15. Role of suppressed hepatocellular regeneration and Ca2+ in chlordecone-potentiated CCl4 hepatotoxicity

    International Nuclear Information System (INIS)

    Bell, A.N.

    1987-01-01

    The mechanism by which the chlorinated pesticide chlordecone (CD; Kepone) potentiates CCl 4 -induced hepatotoxicity and lethality was investigated. It was hypothesized that perturbations in Ca 2+ homeostasis, greater than those observed with a low dose of CCl 4 alone, in concert with a suppression of hepatocellular regeneration induced by CD alone or by CD + CCl 4 are responsible, at least in part, for CD-potentiated CCl 4 hepatotoxicity. Ca 2+ homeostasis was evaluated by measuring total cell Ca 2+ and 45 Ca 2+ uptake in viable isolated hepatocyte suspension obtained from normal and CD-pretreated rats receiving CCl 4 in vivo. In the normal rats in vivo CCL challenge did not affect 45 Ca 2+ uptake by viable isolated hepatocytes. In contrast, 45 Ca 2+ uptake was inhibited in viable isolated hepatocytes obtained from rats exposed to CD + CCl 4

  16. Hepatoprotective effect of leaves of aqueous ethanol extract of Cestrum nocturnum against paracetamol-induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    M. Imran Qadir

    2014-06-01

    Full Text Available The hepatoprotective activities of Cestrum nocturnum (Queen of Night was evaluated against the paracetamol induced hepatotoxicity in the mice. Aqueous ethanol (30:70 extract of plant was obtained by maceration. Results showed that aqueous ethanol extract of C. nocturnum (250 mg/kg and 500 mg/kg produced significant (p<0.05 hepatoprotective activities against paracetamol induced liver injury in Swiss albino mice. Histopathalogical studied of liver further supported the hepatoprotective effects of C. notrunum. Phyto-chemical screening showed the presence of alkaloids, flavonoids, saponins, terpenes, phenolic compounds, carbohydrates and volatile oils. Most of the flavonoids have hepatoprotective activity. Therefore, the hepatoprotective activity of C. nocturnum may be due to the presence of flavonoids and phenolic components. It was concluded from the present study that aqueous ethanol extract of leaves of C. nocturnum has hepatoprotective activity against the paracetamol-induced hepatotoxicity in albino mice.

  17. Oral Delivery of Curcumin Polymeric Nanoparticles Ameliorates CCl4-Induced Subacute Hepatotoxicity in Wistar Rats

    Directory of Open Access Journals (Sweden)

    Gregory Marslin

    2018-05-01

    Full Text Available Curcumin is the major bioactive compound of Curcuma longa, an important medicinal plant used in traditional herbal formulations since ancient times. In the present study, we report that curcumin nanoparticles (ηCur protects Wistar rats against carbon tetrachloride (CCl4-induced subacute hepatotoxicity. Nanoparticles of sizes less than 220 nm with spherical shape were prepared using PLGA and PVA respectively as polymer and stabilizer. Test animals were injected via intraperitoneal route with 1 mL/kg CCl4 (8% in olive oil twice a week over a period of 8 weeks to induce hepatotoxicity. On the days following the CCl4 injection, test animals were orally administered with either curcumin or its equivalent dose of ηCur. Behavioural observation, biochemical analysis of serum and histopathological examination of liver of the experimental animals indicated that ηCur offer significantly higher hepatoprotection compared to curcumin.

  18. The hepatotoxic potential of a Prudhoe Bay crude oil: effect on mouse liver weight and composition

    International Nuclear Information System (INIS)

    Khan, S.; Irfan, M.; Rahimtula, A.D.

    1987-01-01

    The hepatotoxic properties of a Prudhoe Bay Crude Oil (PBCO) were evaluated in mice. Administration of PBCO (5.0 m1/kg body wt, daily for 2 days) to mice resulted in an increase in (i) liver wet and dry weight, (ii) hepatic total proteins RNA, glycogen and lotal lipids, and (iii) individual lipids such as cholesterol, triglycerides and phospholipids. Hepatic protein biosynthesis, determined in vivo by administration of L-[ 14 C] Leucine was increased in PBCO exposed in mice. The rate of 3 H incorporation from 3 H 2 O was significantly enhanced in liver fatty acids, cholesterol, triglycerides and thus ultimately in total lipids. Also, an increase in 3 H incorporation was noticed in hepatic glycogen after PBCO administration. The results suggest that PBCO may induce hepatotoxicity by altering the intermediary metabolism of biochemical constituents. (author) 39 refs

  19. N-Acetyl Cysteine does not prevent liver toxicity from chronic low dose plus sub-acute high dose paracetamol exposure in young or old mice

    Science.gov (United States)

    Kane, Alice-Elizabeth; Huizer-Pajkos, Aniko; Mach, John; McKenzie, Catriona; Mitchell, Sarah-Jayne; de Cabo, Rafael; Jones, Brett; Cogger, Victoria; Le Couteur, David G; Hilmer, Sarah-Nicole

    2016-01-01

    Paracetamol is an analgesic commonly used by people of all ages, which is well documented to cause severe hepatotoxicity with acute over-exposures. The risk of hepatotoxicity from non-acute paracetamol exposures is less extensively studied, and this is the exposure most common in older adults. Evidence on the effectiveness of N-acetyl cysteine (NAC) for non-acute paracetamol exposures, in any age group, is lacking. This study aimed to examine the effect of long-term exposure to therapeutic doses of paracetamol and sub-acute paracetamol over-exposure, in young and old mice, and to investigate whether NAC was effective at preventing paracetamol hepatotoxicity induced by these exposures. Young and old male C57BL/6 mice were fed a paracetamol-containing (1.33g/kg food) or control diet for 6 weeks. Mice were then dosed orally 8 times over 3 days with additional paracetamol (250mg/kg) or saline, followed by either one or two doses of oral NAC (1200mg/kg) or saline. Chronic low-dose paracetamol exposure did not cause hepatotoxicity in young or old mice, measured by serum alanine aminotransferase (ALT) elevation, and confirmed by histology and a DNA fragmentation assay. Sub-acute paracetamol exposure caused significant hepatotoxicity in young and old mice, measured by biochemistry (ALT) and histology. Neither a single nor double dose of NAC protected against this toxicity from sub-acute paracetamol in young or old mice. This finding has important clinical implications for treating toxicity due to different paracetamol exposure types in patients of all ages, and implies a need to develop new treatments for sub-acute paracetamol toxicity. PMID:26821200

  20. Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate

    OpenAIRE

    Humphreys, Jenny H; Warner, Alexander; Costello, Ruth; Lunt, Mark; Verstappen, Suzanne M M; Dixon, William G

    2017-01-01

    Background Patients with rheumatoid arthritis (RA) who take methotrexate (MTX) are advised to limit their alcohol intake due to potential combined hepatotoxicity. However, data are limited to support this. The aim of this study was to quantify the risk of developing abnormal liver blood tests at different levels of alcohol consumption, using routinely collected data from primary care. Methods Patients with RA in the Clinical Practice Research Datalink starting MTX between 1987 and 2016 were i...

  1. Hypolipidemic Effect of Psidium guajava Leaf Extract Against Hepatotoxicity in Rats.

    Science.gov (United States)

    Vijayakumar, K; Rengarajan, R L; Radhakrishnan, R; Anand, A Vijaya

    2018-01-01

    Plant-based natural extracts cure several diseases in human. However, the extract of Psidium guajava leaf is not yet evaluated on changes of lipid profile in hepatic disease affected rats. The present study was aimed to evaluate the mitigation effect of the ethanolic extract of P. guajava leaf and its isolated quercetin fraction on hepatotoxic rats. Carbon tetrachloride (CCl 4 ) was injected to rats for hepatic disease induction and silymarin drug was used as positive control to compare plant ethanolic extract. The lipid profiles were assessed in both plasma and liver tissue of diseased and control rats. Levels of total cholesterol, triglycerides, free fatty acids, phospholipids, and low-density lipoprotein cholesterol were increased and the level of high-density lipoprotein cholesterol (HDL-C) was decreased in CCl 4 -induced hepatotoxic rats. The treatment of P. guajava (100, 200, and 300 mg/kg, bw) and isolated quercetin fraction (20 mg/kg, bw) doses decreased the elevated levels of all these parameters in diseased rats and restored the normal concentration of HDL-C. The results of the present study concluded that the P. guajava leaf and its isolated quercetin fraction can significantly regulate lipid metabolism in CCl 4 -induced hepatotoxic rats and decrease the disease rate. Psidium guajava leaf extract reduces the hepatotoxicity and disease rate in ratsQuercetin fraction of leaf extract significantly regulates lipid profile in hepatic diseased rats. Abbreviations used: CCl 4 : Carbon tetrachloride; FFA: Free fatty acids; HDL-C: High-density lipoprotein cholesterol; LCAT: Lecithin cholesterol acyltransferase; LDL-C: Low-density lipoprotein cholesterol; PL: Phospholipids; TC: Total cholesterol; TG: Triglycerides; VLDL-C: Very low-density lipoprotein cholesterol.

  2. Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb, Polygonum multiflorum.

    Science.gov (United States)

    Li, Chunyu; Niu, Ming; Bai, Zhaofang; Zhang, Congen; Zhao, Yanling; Li, Ruiyu; Tu, Can; Li, Huifang; Jing, Jing; Meng, Yakun; Ma, Zhijie; Feng, Wuwen; Tang, Jinfa; Zhu, Yun; Li, Jinjie; Shang, Xiaoya; Zou, Zhengsheng; Xiao, Xiaohe; Wang, Jiabo

    2017-06-01

    The main constituents of a typical medicinal herb, Polygonum multiflorum (Heshouwu in Chinese), that induces idiosyncratic liver injury remain unclear. Our previous work has shown that cotreatment with a nontoxic dose of lipopolysaccharide (LPS) and therapeutic dose of Heshouwu can induce liver injury in rats, whereas the solo treatment cannot induce observable injury. In the present work, using the constituent "knock-out" and "knock-in" strategy, we found that the ethyl acetate (EA) extract of Heshouwu displayed comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Results indicated a significant elevation of plasma alanine aminotransferase, aspartate aminotransferase, and liver histologic changes, whereas other separated fractions failed to induce liver injury. The mixture of EA extract with other separated fractions induced comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Chemical analysis further revealed that 2,3,5,4'-tetrahydroxy trans-stilbene-2-O-β-glucoside (trans-SG) and its cis-isomer were the two major compounds in EA extract. Furthermore, the isolated cis-, and not its trans-isomer, displayed comparable idiosyncratic hepatotoxicity to EA extract in LPS-treated rats. Higher contents of cis-SG were detected in Heshouwu liquor or preparations from actual liver intoxication patients associated with Heshouwu compared with general collected samples. In addition, plasma metabolomics analysis showed that cis-SG-disturbing enriched pathways remarkably differed from trans-SG ones in LPS-treated rats. All these results suggested that cis-SG was closely associated with the idiosyncratic hepatotoxicity of Heshouwu. Considering that the cis-trans isomerization of trans-SG was mediated by ultraviolet light or sunlight, our findings serve as reference for controlling photoisomerization in drug discovery and for the clinical use of Heshouwu and stilbene-related medications.

  3. The crucial protective role of glutathione against tienilic acid hepatotoxicity in rats

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    Nishiya, Takayoshi; Mori, Kazuhiko; Hattori, Chiharu; Kai, Kiyonori; Kataoka, Hiroko; Masubuchi, Noriko; Jindo, Toshimasa; Manabe, Sunao

    2008-01-01

    To investigate the hepatotoxic potential of tienilic acid in vivo, we administered a single oral dose of tienilic acid to Sprague-Dawley rats and performed general clinicopathological examinations and hepatic gene expression analysis using Affymetrix microarrays. No change in the serum transaminases was noted at up to 1000 mg/kg, although slight elevation of the serum bile acid and bilirubin, and very mild hepatotoxic changes in morphology were observed. In contrast to the marginal clinicopathological changes, marked upregulation of the genes involved in glutathione biosynthesis [glutathione synthetase and glutamate-cysteine ligase (Gcl)], oxidative stress response [heme oxygenase-1 and NAD(P)H dehydrogenase quinone 1] and phase II drug metabolism (glutathione S-transferase and UDP glycosyltransferase 1A6) were noted after 3 or 6 h post-dosing. The hepatic reduced glutathione level decreased at 3-6 h, and then increased at 24 or 48 h, indicating that the upregulation of NF-E2-related factor 2 (Nrf2)-regulated gene and the late increase in hepatic glutathione are protective responses against the oxidative and/or electrophilic stresses caused by tienilic acid. In a subsequent experiment, tienilic acid in combination with L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of Gcl caused marked elevation of serum alanine aminotransferase (ALT) with extensive centrilobular hepatocyte necrosis, whereas BSO alone showed no hepatotoxicity. The elevation of ALT by this combination was observed at the same dose levels of tienilic acid as the upregulation of the Nrf2-regulated genes by tienilic acid alone. In conclusion, these results suggest that the impairment of glutathione biosynthesis may play a critical role in the development of tienilic acid hepatotoxicity through extensive oxidative and/or electrophilic stresses

  4. A critical analysis of the hepatotoxicity cases described in the literature related to Herbalife (r products

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    Flávio Ailton Duque Zambrone

    2015-12-01

    Full Text Available Abstract The aim of this study was to assess the hepatotoxicity cases described in the literature, attributed to the consumption of Herbalife(r products, and to determine whether a causal relationship exists between the reported cases of liver injury and the use of these products. A literature search was performed on the PubMed, LILACS and PAHO databases. Seven publications reporting a total of 53 cases of hepatotoxicity linked to the use of Herbalife(r products were retrieved. All of the studies lacked sufficient information to some degree, whether related to patients' history, concomitant use of medication and/or other compounds (including alcohol, observations on interrupted use (dechallenge, results found with markers, viral serology and autoantibodies or observations concerning re-exposure to the products. In addition to these items, the lack of clear information on the type of products evaluated and their respective composition is an important factor to be considered. Furthermore, data quality was also questionable due to the presence of confounding factors, absence of proper exclusion of alternative explanations, and the use of questionable methods for attributing causality. Hence, an association between hepatotoxicity and consumption of these products cannot be proven based on the data collected and rigorous scientific analysis.

  5. The protective effect of vildagliptin in chronic experimental cyclosporine A-induced hepatotoxicity.

    Science.gov (United States)

    El-Sherbeeny, Nagla A; Nader, Manar A

    2016-03-01

    The study examined the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor, vildagliptin, in cyclosporine (CsA)-induced hepatotoxicity. Rats were divided into 4 groups treated for 28 days: control (vehicle), vildagliptin (10 mg/kg, orally), CsA (20 mg/kg, s.c.), and CsA-vildagliptin group. Liver function was assessed by measuring serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltransferase (γGT), lactate dehydrogenase (LDH), and albumin, and histopathological changes of liver were examined. Oxidative stress markers were evaluated. Assessment of nuclear factor-kappa B (NF-κB) activity in hepatic nuclear extract, serum DPP-4, and expression of Bax and Bcl2 were also done. CsA-induced hepatotoxicity was evidenced by increase in serum levels of AST, ALT, and γGT; a decrease in serum albumin; and a significant alteration in hepatic architecture. Also, significant increase in thiobarbituric acid reactive substance (TBARS) and decrease in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) levels, increased expression Bax proteins with deceased expression of Bcl2, and increased hepatic activity of NF-κB and serum DPP-4 level were observed upon CsA treatment. Vildagliptin significantly improved all altered parameters induced by CsA administration. Vildagliptin has the potential to protect the liver against CsA-induced hepatotoxicity by reducing oxidative stress, DPP-4 activity, apoptosis, and inflammation.

  6. Fumonisin B1 hepatotoxicity in mice is attenuated by depletion of Kupffer cells by gadolinium chloride

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    He, Quanren; Kim, Jiyoung; Sharma, Raghubir P.

    2005-01-01

    Fumonisin B 1 (FB 1 ) is a toxic and carcinogenic mycotoxin produced by Fusarium verticillioides found on corn worldwide. The biological effects of FB 1 are attributed to sphingolipid metabolism disruption as a result of ceramide synthase inhibition. Tumor necrosis factor α (TNFα) is an important modulator of FB 1 hepatotoxicity. Kupffer cells are major source of cytokine production in liver. In the present study we investigated the effects of Kupffer cell depletion by gadolinium on FB 1 hepatotoxicity in female BALB/c mice. Mice were given saline or 50 mg/kg of gadolinium chloride once via the tail vein; 16 h later they were treated with subcutaneous injections of vehicle or 2.25 mg/kg/day FB 1 in saline for three successive days. Gadolinium significantly attenuated FB 1 -induced increases in the activities of circulating alanine aminotransferase and aspartate aminotransferase and reduced the FB 1 -induced hepatocyte apoptosis and free sphinganine accumulation in liver. Both gadolinium and FB 1 treatments individually increased the expression of selected cell signal factors; e.g., TNFα, TNF receptor 1, TNF-related apoptosis-inducing ligand, lymphotoxin β, interferon γ, and transforming growth factor β1; gadolinium chloride did not alter FB 1 -induced expression of the above genes. Results indicated that Kupffer cells play a role in FB 1 hepatotoxicity. Decreased FB 1 -induced sphinganine accumulation and increased protective TNFα signaling by gadolinium chloride may in part account for its ameliorating effect on FB 1 liver damage

  7. Comparative Hepatotoxicity of Fluconazole, Ketoconazole, Itraconazole, Terbinafine, and Griseofulvin in Rats.

    Science.gov (United States)

    Khoza, Star; Moyo, Ishmael; Ncube, Denver

    2017-01-01

    Oral ketoconazole was recently the subject of regulatory safety warnings because of its association with increased risk of inducing hepatic injury. However, the relative hepatotoxicity of antifungal agents has not been clearly established. The aim of this study was to compare the hepatotoxicity induced by five commonly prescribed oral antifungal agents. Rats were treated with therapeutic oral doses of griseofulvin, fluconazole, itraconazole, ketoconazole, and terbinafine. After 14 days, only ketoconazole had significantly higher ALT levels ( p = 0.0017) and AST levels ( p = 0.0008) than the control group. After 28 days, ALT levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, griseofulvin, and terbinafine, respectively. The AST levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, terbinafine, and griseofulvin, respectively. All drugs significantly elevated ALP levels after 14 days and 28 days of treatment ( p terbinafine, and griseofulvin. However, histopathological changes revealed that fluconazole was the most hepatotoxic, followed by ketoconazole, itraconazole, terbinafine, and griseofulvin, respectively. Given the poor correlation between liver enzymes and the extent of liver injury, it is important to confirm liver injury through histological examination.

  8. Comparative Hepatotoxicity of Fluconazole, Ketoconazole, Itraconazole, Terbinafine, and Griseofulvin in Rats

    Directory of Open Access Journals (Sweden)

    Star Khoza

    2017-01-01

    Full Text Available Oral ketoconazole was recently the subject of regulatory safety warnings because of its association with increased risk of inducing hepatic injury. However, the relative hepatotoxicity of antifungal agents has not been clearly established. The aim of this study was to compare the hepatotoxicity induced by five commonly prescribed oral antifungal agents. Rats were treated with therapeutic oral doses of griseofulvin, fluconazole, itraconazole, ketoconazole, and terbinafine. After 14 days, only ketoconazole had significantly higher ALT levels (p=0.0017 and AST levels (p=0.0008 than the control group. After 28 days, ALT levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, griseofulvin, and terbinafine, respectively. The AST levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, terbinafine, and griseofulvin, respectively. All drugs significantly elevated ALP levels after 14 days and 28 days of treatment (p<0.0001. The liver enzyme levels suggested that ketoconazole had the highest risk in causing liver injury followed by itraconazole, fluconazole, terbinafine, and griseofulvin. However, histopathological changes revealed that fluconazole was the most hepatotoxic, followed by ketoconazole, itraconazole, terbinafine, and griseofulvin, respectively. Given the poor correlation between liver enzymes and the extent of liver injury, it is important to confirm liver injury through histological examination.

  9. Effects of ebselen on radiocontrast media-induced hepatotoxicity in rats.

    Science.gov (United States)

    Basarslan, Fatmagul; Yilmaz, Nigar; Davarci, Isil; Akin, Mustafa; Ozgur, Mustafa; Yilmaz, Cahide; Ulutas, Kemal Turker

    2013-09-01

    Oxidative stress is accepted as a potential responsible mechanism in the pathogenesis of radiocontrast media (RCM)-induced hepatotoxicity. Therefore, we aimed to investigate the protective effects of ebselen against RCM-induced hepatotoxicity by measuring tissue oxidant/antioxidant parameters and histological changes in rats. Wistar albino rats were randomly separated into four groups consisting of eight rats per group. Normal saline was given to the rats in control group (group 1). RCM was given to the rats in group 2, and both RCM and ebselen were given to the rats in group 3. Only ebselen was given to the rats in group 4. Liver sections of the killed animals were analyzed to measure the levels of malondialdehyde (MDA) and activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px), as well as histopathological changes. In RCM group, SOD and CAT levels were found increased. In RCM-ebselen group, MDA, SOD and CAT levels were found decreased. In RCM-ebselen group, however, GSH-Px activities of liver tissue increased. All these results indicated that ebselen produced a protective mechanism against RCM-induced hepatotoxicity and took part in oxidative stress.

  10. [Nevirapine related hepatotoxicity: the prevalence and risk factors in a cohort of ART naive Han Chinese with AIDS].

    Science.gov (United States)

    Gao, Shi-cheng; Gui, Xi-en; Deng, Li-ping; Zhang, Yong-xi; Yan, Ya-jun; Rong, Yu-ping; Liang, Ke; Yang, Rong-rong

    2010-09-01

    To investigate the incidence of hepatotoxicity in acquired immunodeficiency syndrome (AIDS) patients on combined anti-retroviral therapy (cART) containing nevirapine (NVP) and to assess the risk factors and its impact on cART. 330 AIDS patients from March 2003 to June 2008 at local county were enrolled and a retrospective study using Kaplan-meier survival and Multivariate logistic regression modeling was conducted. 267 out of 330 patients received NVP based cART and 63 cases received EFV-based cART. The deference of prevalences of hepatotoxicity between the two groups is statistically significant (Chi2 = 6.691, P = 0.01). 133 out of 267 (49.8%) patients on NVP based cART had at least one episode of ALT elevation during a median 21 months (interquartile ranges, IQR 6, 37) follow-up time, amounts for 28.5 cases per 100 person-years. Baseline ALT elevation (OR = 14.368, P = 0.017)and HCV co-infection (OR = 3.009, P = 0.000) were risk factors for cART related hepatotoxicity, while greatly increased CD4+ T(CD4) cell count was protective against hepatotoxicity development (OR = 0.996, P = 0.000). Patients co-infected with HCV received NVP-based cART had the higher probability of hepatotoxicity than those without HCV co-infection (Log rank: Chi2 = 16.764, P = 0.000). 23 out of the 133 subjects (17.3%) with NVP related hepatotoxicity discontinued cART temporarily or shifted NVP to efavirenz. NVP related hepatotoxicity was common among ARV naive HIV infected subjects in our cohort. Baseline ALT elevation and HCV co-infection were associated statistically with the development of hepatotoxicity. Hepatotoxicity led to discontinuing cART temporarily or switching to other regimens in some subjects. It suggested that NVP should be used with caution in patients co-infected with HCV among whom anti-HCV therapy before cART initiation may contribute to minimizing the probability of NVP associated hepatotoxicity.

  11. Possible Phenylacetate Hepatotoxicity During 4-Phenylbutyrate Therapy of Byler Disease.

    Science.gov (United States)

    Shneider, Benjamin L; Morris, Amy; Vockley, Jerry

    2016-03-01

    In vitro studies have suggested that 4-phenylbutyrate (PBA) may rescue missense mutated proteins that underlie some forms of progressive familial intrahepatic cholestasis. Encouraging preliminary responses to 4-PBA have been reported in liver disease secondary to mutations in ABCB11 and ATP8B1. A 4-year-old boy with Byler disease was treated with 4-PBA in the forms of sodium PBA (5 months) and then glycerol PBA (7 months) as part of expanded access single patient protocols. During this therapy serum total bilirubin fell and his general well-being was reported to be improved, although total serum bile acids were not reduced. Discontinuation of rifampin therapy, which had been used to treat pruritus, resulted in reversible severe acute liver injury that was potentially the result of phenylacetate toxicity. Interactions between 4-PBA and cytochrome P450 enzymes should be considered in the use of this agent with special attention to potential phenylacetate toxicity.

  12. Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol-induced hepatotoxicity

    Science.gov (United States)

    Craig, Darren G N; Bates, Caroline M; Davidson, Janice S; Martin, Kirsty G; Hayes, Peter C; Simpson, Kenneth J

    2012-01-01

    AIMS Paracetamol (acetaminophen) poisoning remains the major cause of severe acute hepatotoxicity in the UK. In this large single centre cohort study we examined the clinical impact of staggered overdoses and delayed presentation following paracetamol overdose. RESULTS Between 1992 and 2008, 663 patients were admitted with paracetamol-induced severe liver injury, of whom 161 (24.3%) had taken a staggered overdose. Staggered overdose patients were significantly older and more likely to abuse alcohol than single time point overdose patients. Relief of pain (58.2%) was the commonest rationale for repeated supratherapeutic ingestion. Despite lower total ingested paracetamol doses and lower admission serum alanine aminotransferase concentrations, staggered overdose patients were more likely to be encephalopathic on admission, require renal replacement therapy or mechanical ventilation and had higher mortality rates compared with single time point overdoses (37.3% vs. 27.8%, P = 0.025), although this overdose pattern did not independently predict death. The King's College poor prognostic criteria had reduced sensitivity (77.6, 95% CI 70.8, 81.5) for this pattern of overdose. Of the 396/450 (88.0%) single time point overdoses in whom accurate timings could be obtained, 178 (44.9%) presented to medical services >24 h following overdose. Delayed presentation beyond 24 h post overdose was independently associated with death/liver transplantation (OR 2.25, 95% CI 1.23, 4.12, P = 0.009). CONCLUSIONS Both delayed presentation and staggered overdose pattern are associated with adverse outcomes following paracetamol overdose. These patients are at increased risk of developing multi-organ failure and should be considered for early transfer to specialist liver centres. PMID:22106945

  13. Chlorpromazine-induced hepatotoxicity during inflammation is mediated by TIRAP-dependent signaling pathway in mice

    International Nuclear Information System (INIS)

    Gandhi, Adarsh; Guo, Tao; Shah, Pranav; Moorthy, Bhagavatula; Ghose, Romi

    2013-01-01

    Inflammation is a major component of idiosyncratic adverse drug reactions (IADRs). To understand the molecular mechanism of inflammation-mediated IADRs, we determined the role of the Toll-like receptor (TLR) signaling pathway in idiosyncratic hepatotoxicity of the anti-psychotic drug, chlorpromazine (CPZ). Activation of TLRs recruits the first adaptor protein, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) to the TIR domain of TLRs leading to the activation of the downstream kinase, c-Jun-N-terminal kinase (JNK). Prolonged activation of JNK leads to cell-death. We hypothesized that activation of TLR2 by lipoteichoic acid (LTA) or TLR4 by lipopolysaccharide (LPS) will augment the hepatotoxicity of CPZ by TIRAP-dependent mechanism involving prolonged activation of JNK. Adult male C57BL/6, TIRAP +/+ and TIRAP −/− mice were pretreated with saline, LPS (2 mg/kg) or LTA (6 mg/kg) for 30 min or 16 h followed by CPZ (5 mg/kg) or saline (vehicle) up to 24 h. We found that treatment of mice with CPZ in presence of LPS or LTA leads to ∼ 3–4 fold increase in serum ALT levels, a marked reduction in hepatic glycogen content, significant induction of serum tumor necrosis factor (TNF) α and prolonged JNK activation, compared to LPS or LTA alone. Similar results were observed in TIRAP +/+ mice, whereas the effects of LPS or LTA on CPZ-induced hepatotoxicity were attenuated in TIRAP −/− mice. For the first time, we show that inflammation-mediated hepatotoxicity of CPZ is dependent on TIRAP, and involves prolonged JNK activation in vivo. Thus, TIRAP-dependent pathways may be targeted to predict and prevent inflammation-mediated IADRs. -- Highlights: ► Inflammation augments the toxicity of an idiosyncratic hepatotoxin chlorpromazine. ► Activation of Toll-like receptors by LPS or LTA induces chlorpromazine toxicity. ► Sustained stress kinase (JNK) activation is associated with chlorpromazine toxicity. ► These studies provide novel mechanistic

  14. The Relation between Hepatotoxicity and the Total Coumarin Intake from Traditional Japanese Medicines Containing Cinnamon Bark.

    Science.gov (United States)

    Iwata, Naohiro; Kainuma, Mosaburo; Kobayashi, Daisuke; Kubota, Toshio; Sugawara, Naoko; Uchida, Aiko; Ozono, Sahoko; Yamamuro, Yuki; Furusyo, Norihiro; Ueda, Koso; Tahara, Eiichi; Shimazoe, Takao

    2016-01-01

    Cinnamon bark is commonly used in traditional Japanese herbal medicines (Kampo medicines). The coumarin contained in cinnamon is known to be hepatotoxic, and a tolerable daily intake (TDI) of 0.1 mg/kg/day, has been quantified and used in Europe to insure safety. Risk assessments for hepatotoxicity by the cinnamon contained in foods have been reported. However, no such assessment of cinnamon bark has been reported and the coumarin content of Kampo medicines derived from cinnamon bark is not yet known. To assess the risk for hepatotoxicity by Kampo medicines, we evaluated the daily coumarin intake of patients who were prescribed Kampo medicines and investigated the relation between hepatotoxicity and the coumarin intake. The clinical data of 129 outpatients (18 male and 111 female, median age 58 years) who had been prescribed keishibukuryogankayokuinin (TJ-125) between April 2008 and March 2013 was retrospectively investigated. Concurrent Kampo medicines and liver function were also surveyed. In addition to TJ-125, the patients took some of the other 32 Kampo preparations and 22 decoctions that include cinnamon bark. The coumarin content of these Kampo medicines was determined by high performance liquid chromatography (HPLC). TJ-125 had the highest daily content of coumarin (5.63 mg/day), calculated from the daily cinnamon bark dosage reported in the information leaflet inserted in each package of Kampo medicine. The coumarin content in 1g cinnamon bark decoction was 3.0 mg. The daily coumarin intake of the patients was 0.113 (0.049-0.541) mg/kg/day, with 98 patients (76.0%) exceeding the TDI. Twenty-three patients had an abnormal change in liver function test value, but no significant difference was found in the incidence of abnormal change between the group consuming less than the TDI value (6/31, 19.4%) and the group consuming equal to or greater than the TDI value (17/98, 17.3%). In addition, no abnormal change related to cinnamon bark was found for individual

  15. Chlorpromazine-induced hepatotoxicity during inflammation is mediated by TIRAP-dependent signaling pathway in mice

    Energy Technology Data Exchange (ETDEWEB)

    Gandhi, Adarsh, E-mail: adarsh.gandhi@nih.gov [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States); Guo, Tao, E-mail: tguo4@jhu.edu [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States); Shah, Pranav [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States); Moorthy, Bhagavatula [Baylor College of Medicine, Department of Pediatrics, 1102 Bates Avenue, Suite 530, Houston, TX 77030 (United States); Ghose, Romi, E-mail: rghose@uh.edu [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States)

    2013-02-01

    Inflammation is a major component of idiosyncratic adverse drug reactions (IADRs). To understand the molecular mechanism of inflammation-mediated IADRs, we determined the role of the Toll-like receptor (TLR) signaling pathway in idiosyncratic hepatotoxicity of the anti-psychotic drug, chlorpromazine (CPZ). Activation of TLRs recruits the first adaptor protein, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) to the TIR domain of TLRs leading to the activation of the downstream kinase, c-Jun-N-terminal kinase (JNK). Prolonged activation of JNK leads to cell-death. We hypothesized that activation of TLR2 by lipoteichoic acid (LTA) or TLR4 by lipopolysaccharide (LPS) will augment the hepatotoxicity of CPZ by TIRAP-dependent mechanism involving prolonged activation of JNK. Adult male C57BL/6, TIRAP{sup +/+} and TIRAP{sup −/−} mice were pretreated with saline, LPS (2 mg/kg) or LTA (6 mg/kg) for 30 min or 16 h followed by CPZ (5 mg/kg) or saline (vehicle) up to 24 h. We found that treatment of mice with CPZ in presence of LPS or LTA leads to ∼ 3–4 fold increase in serum ALT levels, a marked reduction in hepatic glycogen content, significant induction of serum tumor necrosis factor (TNF) α and prolonged JNK activation, compared to LPS or LTA alone. Similar results were observed in TIRAP{sup +/+} mice, whereas the effects of LPS or LTA on CPZ-induced hepatotoxicity were attenuated in TIRAP{sup −/−} mice. For the first time, we show that inflammation-mediated hepatotoxicity of CPZ is dependent on TIRAP, and involves prolonged JNK activation in vivo. Thus, TIRAP-dependent pathways may be targeted to predict and prevent inflammation-mediated IADRs. -- Highlights: ► Inflammation augments the toxicity of an idiosyncratic hepatotoxin chlorpromazine. ► Activation of Toll-like receptors by LPS or LTA induces chlorpromazine toxicity. ► Sustained stress kinase (JNK) activation is associated with chlorpromazine toxicity. ► These studies

  16. Cannabidiol Rescues Acute Hepatic Toxicity and Seizure Induced by Cocaine

    Directory of Open Access Journals (Sweden)

    Luciano Rezende Vilela

    2015-01-01

    Full Text Available Cocaine is a commonly abused illicit drug that causes significant morbidity and mortality. The most severe and common complications are seizures, ischemic strokes, myocardial infarction, and acute liver injury. Here, we demonstrated that acute cocaine intoxication promoted seizure along with acute liver damage in mice, with intense inflammatory infiltrate. Considering the protective role of the endocannabinoid system against cell toxicity, we hypothesized that treatment with an anandamide hydrolysis inhibitor, URB597, or with a phytocannabinoid, cannabidiol (CBD, protects against cocaine toxicity. URB597 (1.0 mg/kg abolished cocaine-induced seizure, yet it did not protect against acute liver injury. Using confocal liver intravital microscopy, we observed that CBD (30 mg/kg reduced acute liver inflammation and damage induced by cocaine and prevented associated seizure. Additionally, we showed that previous liver damage induced by another hepatotoxic drug (acetaminophen increased seizure and lethality induced by cocaine intoxication, linking hepatotoxicity to seizure dynamics. These findings suggest that activation of cannabinoid system may have protective actions on both liver and brain induced by cocaine, minimizing inflammatory injury promoted by cocaine, supporting its further clinical application in the treatment of cocaine abuse.

  17. Acetaminophen (Paracetamol) Induces Hypothermia During Acute Cold Stress.

    Science.gov (United States)

    Foster, Josh; Mauger, Alexis R; Govus, Andrew; Hewson, David; Taylor, Lee

    2017-11-01

    Acetaminophen is an over-the-counter drug used to treat pain and fever, but it has also been shown to reduce core temperature (T c ) in the absence of fever. However, this side effect is not well examined in humans, and it is unknown if the hypothermic response to acetaminophen is exacerbated with cold exposure. To address this question, we mapped the thermoregulatory responses to acetaminophen and placebo administration during exposure to acute cold (10 °C) and thermal neutrality (25 °C). Nine healthy Caucasian males (aged 20-24 years) participated in the experiment. In a double-blind, randomised, repeated measures design, participants were passively exposed to a thermo-neutral or cold environment for 120 min, with administration of 20 mg/kg lean body mass acetaminophen or a placebo 5 min prior to exposure. T c , skin temperature (T sk ), heart rate, and thermal sensation were measured every 10 min, and mean arterial pressure was recorded every 30 min. Data were analysed using linear mixed effects models. Differences in thermal sensation were analysed using a cumulative link mixed model. Acetaminophen had no effect on T c in a thermo-neutral environment, but significantly reduced T c during cold exposure, compared with a placebo. T c was lower in the acetaminophen compared with the placebo condition at each 10-min interval from 80 to 120 min into the trial (all p  0.05). This preliminary trial suggests that acetaminophen-induced hypothermia is exacerbated during cold stress. Larger scale trials seem warranted to determine if acetaminophen administration is associated with an increased risk of accidental hypothermia, particularly in vulnerable populations such as frail elderly individuals.

  18. Ginger for Prevention of Antituberculosis-induced Gastrointestinal Adverse Reactions Including Hepatotoxicity: A Randomized Pilot Clinical Trial.

    Science.gov (United States)

    Emrani, Zahra; Shojaei, Esphandiar; Khalili, Hossein

    2016-06-01

    In this study, the potential benefits of ginger in preventing antituberculosis drug-induced gastrointestinal adverse reactions including hepatotoxicity have been evaluated in patients with tuberculosis. Patients in the ginger and placebo groups (30 patients in each group) received either 500 mg ginger (Zintoma)(®) or placebo one-half hour before each daily dose of antituberculosis drugs for 4 weeks. Patients' gastrointestinal complaints (nausea, vomiting, dyspepsia, and abdominal pain) and antituberculosis drug-induced hepatotoxicity were recorded during the study period. In this cohort, nausea was the most common antituberculosis drug-induced gastrointestinal adverse reactions. Forty eight (80%) patients experienced nausea. Nausea was more common in the placebo than the ginger group [27 (90%) vs 21 (70%), respectively, p = 0.05]. During the study period, 16 (26.7%) patients experienced antituberculosis drug-induced hepatotoxicity. Patients in the ginger group experienced less, but not statistically significant, antituberculosis drug-induced hepatotoxicity than the placebo group (16.7% vs 36.7%, respectively, p = 0.07). In conclusion, ginger may be a potential option for prevention of antituberculosis drug-induced gastrointestinal adverse reactions including hepatotoxicity. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  19. The biochemistry of acetaminophen hepatotoxicity and rescue: a mathematical model

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    Ben-Shachar Rotem

    2012-12-01

    Full Text Available Abstract Background Acetaminophen (N-acetyl-para-aminophenol is the most widely used over-the-counter or prescription painkiller in the world. Acetaminophen is metabolized in the liver where a toxic byproduct is produced that can be removed by conjugation with glutathione. Acetaminophen overdoses, either accidental or intentional, are the leading cause of acute liver failure in the United States, accounting for 56,000 emergency room visits per year. The standard treatment for overdose is N-acetyl-cysteine (NAC, which is given to stimulate the production of glutathione. Methods We have created a mathematical model for acetaminophen transport and metabolism including the following compartments: gut, plasma, liver, tissue, urine. In the liver compartment the metabolism of acetaminophen includes sulfation, glucoronidation, conjugation with glutathione, production of the toxic metabolite, and liver damage, taking biochemical parameters from the literature whenever possible. This model is then connected to a previously constructed model of glutathione metabolism. Results We show that our model accurately reproduces published clinical and experimental data on the dose-dependent time course of acetaminophen in the plasma, the accumulation of acetaminophen and its metabolites in the urine, and the depletion of glutathione caused by conjugation with the toxic product. We use the model to study the extent of liver damage caused by overdoses or by chronic use of therapeutic doses, and the effects of polymorphisms in glucoronidation enzymes. We use the model to study the depletion of glutathione and the effect of the size and timing of N-acetyl-cysteine doses given as an antidote. Our model accurately predicts patient death or recovery depending on size of APAP overdose and time of treatment. Conclusions The mathematical model provides a new tool for studying the effects of various doses of acetaminophen on the liver metabolism of acetaminophen and

  20. Induction of Mrp3 and Mrp4 transporters during acetaminophen hepatotoxicity is dependent on Nrf2

    International Nuclear Information System (INIS)

    Aleksunes, Lauren M.; Slitt, Angela L.; Maher, Jonathan M.; Augustine, Lisa M.; Goedken, Michael J.; Chan, Jefferson Y.; Cherrington, Nathan J.; Klaassen, Curtis D.; Manautou, Jose E.

    2008-01-01

    The transcription factor NFE2-related factor 2 (Nrf2) mediates detoxification and antioxidant gene transcription following electrophile exposure and oxidative stress. Mice deficient in Nrf2 (Nrf2-null) are highly susceptible to acetaminophen (APAP) hepatotoxicity and exhibit lower basal and inducible expression of cytoprotective genes, including NADPH quinone oxidoreductase 1 (Nqo1) and glutamate cysteine ligase (catalytic subunit, or Gclc). Administration of toxic APAP doses to C57BL/6J mice generates electrophilic stress and subsequently increases levels of hepatic Nqo1, Gclc and the efflux multidrug resistance-associated protein transporters 1-4 (Mrp1-4). It was hypothesized that induction of hepatic Mrp1-4 expression following APAP is Nrf2 dependent. Plasma and livers from wild-type (WT) and Nrf2-null mice were collected 4, 24 and 48 h after APAP. As expected, hepatotoxicity was greater in Nrf2-null compared to WT mice. Gene and protein expression of Mrp1-4 and the Nrf2 targets, Nqo1 and Gclc, was measured. Induction of Nqo1 and Gclc mRNA and protein after APAP was dependent on Nrf2 expression. Similarly, APAP treatment increased hepatic Mrp3 and Mrp4 mRNA and protein in WT, but not Nrf2-null mice. Mrp1 was induced in both genotypes after APAP, suggesting that elevated expression of this transporter was independent of Nrf2. Mrp2 was not induced in either genotype at the mRNA or protein levels. These results show that Nrf2 mediates induction of Mrp3 and Mrp4 after APAP but does not affect Mrp1 or Mrp2. Thus coordinated regulation of detoxification enzymes and transporters by Nrf2 during APAP hepatotoxicity is a mechanism by which hepatocytes may limit intracellular accumulation of potentially toxic chemicals

  1. Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate.

    Science.gov (United States)

    Humphreys, Jenny H; Warner, Alexander; Costello, Ruth; Lunt, Mark; Verstappen, Suzanne M M; Dixon, William G

    2017-09-01

    Patients with rheumatoid arthritis (RA) who take methotrexate (MTX) are advised to limit their alcohol intake due to potential combined hepatotoxicity. However, data are limited to support this. The aim of this study was to quantify the risk of developing abnormal liver blood tests at different levels of alcohol consumption, using routinely collected data from primary care. Patients with RA in the Clinical Practice Research Datalink starting MTX between 1987 and 2016 were included. Hepatotoxicity was defined as transaminitis: alanine transaminase or aspartate aminotransferase more than three times the upper limit of normal. Crude rates of transaminitis were calculated per 1000 person-years, categorised by weekly alcohol consumption in units. Cox proportional hazard models tested the association between alcohol consumption and transaminitis univariately, then age and gender adjusted. 11 839 patients were included, with 530 episodes of transaminitis occurring in 47 090 person-years follow-up. Increased weekly alcohol consumption as a continuous variable was associated with increased risk of transaminitis, adjusted HR (95% CI) per unit consumed 1.01 (1.00 to 1.02); consuming between 15 and 21 units was associated with a possible increased risk of hepatotoxicity, while drinking >21 units per week significantly increased rates of transaminitis, adjusted HR (95% CI) 1.85 (1.17 to 2.93). Weekly alcohol consumption of risk of transaminitis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  2. Ameliorative effect of vitamin C against hepatotoxicity induced by emamectin benzoate in rats.

    Science.gov (United States)

    Khaldoun Oularbi, H; Richeval, C; Lebaili, N; Zerrouki-Daoudi, N; Baha, M; Djennas, N; Allorge, D

    2017-07-01

    In the present study, we aimed to assess the potential protective effect of ascorbic acid (AA) against emamectin benzoate (EMB)-induced hepatotoxicity. For this purpose, biochemical, histopathological and analytical investigations were performed. Male Wistar rats were distributed into three groups, that is, a control group, an EMB group given 10 mg EMB/kg body weight (BW) by gavage and an EMB + AA group given 10 mg EMB/kg BW and vitamin C intraperitoneally (200 mg/kg). The duration of the treatment was 28 days and the duration of the study was 42 days. There was a statistically significant increase of all hepatic biomarkers, that is, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyltransferase activities, and glycemia, in EMB-treated group when compared with the control group. Light microscopic observations revealed variable signs of hepatotoxicity in the EMB group, which were represented by alteration of normal hepatic architecture, inflammatory cell infiltration, hepatocellular steatosis and foci of necrosis at 28 and 42 days post-treatment. However, co-treatment with vitamin C reduced EMB-related liver toxicity and diminished the abnormal biochemical and architectural damage. Emamectin B1a and B1b residues were detectable in all plasma samples of treated rats at 14, 21 and 28 days of treatment. The drug liver tissue concentration was significantly lower in EMB + AA group compared with EMB group at 28 and 42 days. In conclusion, the findings of the present study clearly indicate a significant protective action of vitamin C against EMB hepatotoxicity.

  3. Bees' Honey Attenuation of Metanil-Yellow-Induced Hepatotoxicity in Rats

    OpenAIRE

    Al-Malki, Abdulrahman L.; Sayed, Ahmed Amir Radwan

    2013-01-01

    The present study aims to investigate the protective effect of bees' honey against metanil-yellow-induced hepatotoxicity in rats. Rats were divided into 7 groups: control group; three groups treated with 50, 100, and 200?mg/kg metanil yellow, and three groups treated with metanil yellow plus 2.5?mg ? kg?1 ? day?1 bees' honey for 8 weeks. The obtained data showed that the antioxidant/anti-inflammatory activity of bees' honey reduced the oxidative stress in the liver tissue and downregulated th...

  4. Severe hepatotoxic adverse reaction in a healthy schoolgirl after treatment with flucloxacillin

    Directory of Open Access Journals (Sweden)

    C-J Törnhage

    2009-03-01

    Full Text Available C-J Törnhage1, G Brunlöf2, S M Wallerstedt21Department of Paediatrics, Central Hospital, Skaraborg, Skövde, Sweden; 2Department of Clinical Pharmacology, Sahlgrenska University Hospital, Göteborg, SwedenAbstract: This is the first detailed description of a severe hepatotoxic reaction in a previously healthy 9-year-old schoolgirl after ingestion of some flucloxacillin tablets. She was clinically well within one week and alanine aminotransferase in serum was normalized in one month. Follow up for more than one year was normal.Keywords: adverse reaction, children, flucloxacillin, hepatopathy

  5. Ketoconazole hepatotoxicity in a patient treated for environmental illness and systemic candidiasis

    Energy Technology Data Exchange (ETDEWEB)

    Brusko, C.S.; Marten, J.T. (Purdue University School of Pharmacy and Pharmacal Sciences, Lafayette, IN (United States))

    1991-12-01

    Environmental illness, a hypothesized disease caused by exposure to substances such as combustion products, pesticides, food additives, and Candida albicans, is discussed. The case of a patient with environmental illness and systemic candidiasis for six weeks with ketoconazole, liver enzyme concentrations increased. One month after discontinuation of ketoconazole, the liver enzyme concentrations decreased; however, over the next five months, liver enzymes and bilirubin increased. The patient developed encephalopathy and eventually was transferred to a medical center for possible liver transplant. A review of the literature pertaining to ketoconazole hepatotoxicity is also presented.16 references.

  6. Higher Thyroid-Stimulating Hormone, Triiodothyronine and Thyroxine Values Are Associated with Better Outcome in Acute Liver Failure.

    Science.gov (United States)

    Anastasiou, Olympia; Sydor, Svenja; Sowa, Jan-Peter; Manka, Paul; Katsounas, Antonios; Syn, Wing-Kin; Führer, Dagmar; Gieseler, Robert K; Bechmann, Lars P; Gerken, Guido; Moeller, Lars C; Canbay, Ali

    2015-01-01

    Changes in thyroid hormone levels, mostly as non-thyroidal illness syndrome (NTIS), have been described in many diseases. However, the relationship between acute liver failure (ALF) and thyroid hormone levels has not yet been clarified. The present study evaluates potential correlations of select thyroid functional parameters with ALF. 84 consecutively recruited ALF patients were grouped according to the outcome of ALF (spontaneous recovery: SR; transplantation or death: NSR). TSH, free thyroxine (fT4), free triiodothyronine (fT3), T4, and T3 were determined. More than 50% of patients with ALF presented with abnormal thyroid parameters. These patients had greater risk for an adverse outcome than euthyroid patients. SR patients had significantly higher TSH, T4, and T3 concentrations than NSR patients. Albumin concentrations were significantly higher in SR than in NSR. In vitro T3 treatment was not able to rescue primary human hepatocytes from acetaminophen induced changes in mRNA expression. In patients with ALF, TSH and total thyroid hormone levels differed significantly between SR patients and NSR patients. This might be related to diminished liver-derived transport proteins, such as albumin, in more severe forms of ALF. Thyroid parameters may serve as additional indicators of ALF severity.

  7. Metabolomics approaches for discovering biomarkers of drug-induced hepatotoxicity and nephrotoxicity

    International Nuclear Information System (INIS)

    Beger, Richard D.; Sun, Jinchun; Schnackenberg, Laura K.

    2010-01-01

    Hepatotoxicity and nephrotoxicity are two major reasons that drugs are withdrawn post-market, and hence it is of major concern to both the FDA and pharmaceutical companies. The number of cases of serious adverse effects (SAEs) in marketed drugs has climbed faster than the number of total drug prescriptions issued. In some cases, preclinical animal studies fail to identify the potential toxicity of a new chemical entity (NCE) under development. The current clinical chemistry biomarkers of liver and kidney injury are inadequate in terms of sensitivity and/or specificity, prompting the need to discover new translational specific biomarkers of organ injury. Metabolomics along with genomics and proteomics technologies have the capability of providing translational diagnostic and prognostic biomarkers specific for early stages of liver and kidney injury. Metabolomics has several advantages over the other omics platforms such as ease of sample preparation, data acquisition and use of biofluids collected through minimally invasive procedures in preclinical and clinical studies. The metabolomics platform is reviewed with particular emphasis on applications involving drug-induced hepatotoxicity and nephrotoxicity. Analytical platforms for metabolomics, chemometrics for mining metabolomics data and the applications of the metabolomics technologies are covered in detail with emphasis on recent work in the field.

  8. Metabolomics of Hydrazine-Induced Hepatotoxicity in Rats for Discovering Potential Biomarkers

    Directory of Open Access Journals (Sweden)

    Zhuoling An

    2018-01-01

    Full Text Available Metabolic pathway disturbances associated with drug-induced liver injury remain unsatisfactorily characterized. Diagnostic biomarkers for hepatotoxicity have been used to minimize drug-induced liver injury and to increase the clinical safety. A metabolomics strategy using rapid-resolution liquid chromatography/tandem mass spectrometry (RRLC-MS/MS analyses and multivariate statistics was implemented to identify potential biomarkers for hydrazine-induced hepatotoxicity. The global serum and urine metabolomics of 30 hydrazine-treated rats at 24 or 48 h postdosing and 24 healthy rats were characterized by a metabolomics approach. Multivariate statistical data analyses and receiver operating characteristic (ROC curves were performed to identify the most significantly altered metabolites. The 16 most significant potential biomarkers were identified to be closely related to hydrazine-induced liver injury. The combination of these biomarkers had an area under the curve (AUC > 0.85, with 100% specificity and sensitivity, respectively. This high-quality classification group included amino acids and their derivatives, glutathione metabolites, vitamins, fatty acids, intermediates of pyrimidine metabolism, and lipids. Additionally, metabolomics pathway analyses confirmed that phenylalanine, tyrosine, and tryptophan biosynthesis as well as tyrosine metabolism had great interactions with hydrazine-induced liver injury in rats. These discriminating metabolites might be useful in understanding the pathogenesis mechanisms of liver injury and provide good prospects for drug-induced liver injury diagnosis clinically.

  9. Severe hepatotoxicity following ingestion of Herbalife nutritional supplements contaminated with Bacillus subtilis.

    Science.gov (United States)

    Stickel, Felix; Droz, Sara; Patsenker, Eleonora; Bögli-Stuber, Katja; Aebi, Beat; Leib, Stephen L

    2009-01-01

    Nutritional supplements are widely used. Recently, liver injury after consumption of Herbalife preparations was reported but the underlying pathogenesis remained cryptic. Two patients presented with cholestatic hepatitis and pruritus, and cirrhosis, respectively. Viral, alcoholic, metabolic, autoimmune, neoplastic, vascular liver diseases and synthetic drugs as the precipitating causes of liver injury were excluded. However, both patients reported long-term consumption of Herbalife products. All Herbalife products were tested for contamination with drugs, pesticides, heavy metals, and softeners, and examined for microbial contamination according to standard laboratory procedures. Bacteria isolated from the samples were identified as Bacillus subtilis by sequencing the 16S rRNA and gyrB genes. Causality between consumption of Herbalife products and disease according to CIOMS was scored "probable" in both cases. Histology showed cholestatic and lobular/portal hepatitis with cirrhosis in one patient, and biliary fibrosis with ductopenia in the other. No contamination with chemicals or heavy metals was detected, and immunological testing showed no drug hypersensitivity. However, samples of Herbalife products ingested by both patients showed growth of Bacillus subtilis of which culture supernatants showed dose- and time-dependent hepatotoxicity. Two novel incidents of severe hepatic injury following intake of Herbalife products contaminated with Bacillus subtilis emphasize its potential hepatotoxicity.

  10. Therapeutic Effects of Cassia angustifolia in a Cadmium Induced Hepatotoxicity Assay Conducted in Male Albino Rats

    Directory of Open Access Journals (Sweden)

    Muhammad Tahir Haidry

    2016-04-01

    Full Text Available The present study aims to investigate the therapeutic effects of Senna plant (Cassia angustifolia L. in a cadmium-induced hepatotoxicity assay by evaluating the activity of alanine transaminase (ALT, aspartate transaminase (AST, alkaline phosphatase (ALP and total protein (TP in the albino rats’ serum. A total of 30 white albino rats were taken and divided into three groups; each group comprising ten rats. The group A was taken as a control group; group B was given cadmium chloride concentration of 5 mg/kg (body weight for 42 days; and group C was given cadmium chloride 5 mg/kg body weight for first 21 days and then extract of C. angustifolia 100 mg/kg (body weight was given for remaining 21 days. The analysis were performed twice i.e., on 21stst day and 42nd day. Results illustrated that the concentration of cadmium was significantly elevated (P<0.05 at the levels of serum biochemical markers namely ALT, AST, ALP which lowered the protein levels in albino rats. Moreover, treatment with the standard extracts of C. angustifolia observed to reverse the effects of the cadmium significantly (P<0.05. It is concluded that the C. angustifolia had hepatoprotective effects and therapeutic potential against the cadmium-induced hepatotoxicity in albino rats.

  11. Microscale 3D Liver Bioreactor for In Vitro Hepatotoxicity Testing under Perfusion Conditions

    Directory of Open Access Journals (Sweden)

    Nora Freyer

    2018-03-01

    Full Text Available The accurate prediction of hepatotoxicity demands validated human in vitro models that can close the gap between preclinical animal studies and clinical trials. In this study we investigated the response of primary human liver cells to toxic drug exposure in a perfused microscale 3D liver bioreactor. The cellularized bioreactors were treated with 5, 10, or 30 mM acetaminophen (APAP used as a reference substance. Lactate production significantly decreased upon treatment with 30 mM APAP (p < 0.05 and ammonia release significantly increased in bioreactors treated with 10 or 30 mM APAP (p < 0.0001, indicating APAP-induced dose-dependent toxicity. The release of prostaglandin E2 showed a significant increase at 30 mM APAP (p < 0.05, suggesting an inflammatory reaction towards enhanced cellular stress. The expression of genes involved in drug metabolism, antioxidant reactions, urea synthesis, and apoptosis was differentially influenced by APAP exposure. Histological examinations revealed that primary human liver cells in untreated control bioreactors were reorganized in tissue-like cell aggregates. These aggregates were partly disintegrated upon APAP treatment, lacking expression of hepatocyte-specific proteins and transporters. In conclusion, our results validate the suitability of the microscale 3D liver bioreactor to detect hepatotoxic effects of drugs in vitro under perfusion conditions.

  12. [Individualized clinical treatment from the prospective of hepatotoxicity of non-toxic traditional Chinese medicine].

    Science.gov (United States)

    Yang, Nan; Chen, Juan; Hou, Xue-Feng; Song, Jie; Feng, Liang; Jia, Xiao-Bin

    2017-04-01

    Traditional Chinese medicine has a long history in clinical application, and been proved to be safe and effective. In recent years, the toxicity and side-effects caused by the western medicine have been attracted much attention. As a result, increasing people have shifted their attention to traditional Chinese medicine. Nonetheless, due to the natural origin of traditional Chinese medicine and the lack of basic knowledge about them, many people mistakenly consider the absolute safety of traditional Chinese medicine, except for well-known toxic ones, such as arsenic. However, according to the clinical practices and recent studies, great importance shall be attached to the toxicity of non-toxic traditional Chinese medicine, in particular the hepatotoxicity. Relevant studies indicated that the toxicity of non-toxic traditional Chinese medicine is closely correlated with individual gene polymorphism and constitution. By discussing the causes and mechanisms of the hepatotoxicity induced by non-toxic traditional Chinese medicine in clinical practices, we wrote this article with the aim to provide new ideas for individualized clinical therapy of traditional Chinese medicine and give guidance for rational and safe use of traditional Chinese medicine. Copyright© by the Chinese Pharmaceutical Association.

  13. The protective effects of vitamin C on hepatotoxicity induced by radiation

    International Nuclear Information System (INIS)

    Ahn, Ki Jung; Park, Sung Kwang; Cho, Heung Lae; Kang, Ki Mun; Chai, Gyu Young; Chung, Duck Wha; Kang, Jin Soon

    2004-01-01

    This study was carried out to determine the protective effects of vitamin C on the hepatotoxicity induced by radiation. The Spraque Dawley rats were randomly divided into 3 groups; the control group, the radiation exposed group, and the radiation and vitamin C-treated group. SOD activity catalase, malondialdehyde and liver enzymes were analyzed to assess the antioxidant effects of vitamin C. The increased level of malondialdehyde and the decreased catalase activity that were induced by radiation were improved after vitamin C but were was no statistical significance among three groups. The superoxide dismutase activity of the liver was increased by vitamin C, but there were no statistically significant differences between the vitamin C-treated group and the non vitamin C-treated group. The level of liver enzymes in sera such as glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, lactate dehyrogenase and alkaline phosphatase were remarkably elevated by radiation. The levels of those enzymes were decreased in the vitamin C-treated group and statistical significance was noted for the GPT level (ρ < 0.01). On the electromicrographic findings, the hepatic cell destruction was considerably decreased in the vitamin C-treated group. Vitamin C is thought to be an effective antioxidant against the hepatotoxicity induced by radiation

  14. Moringa oleifera-based diet protects against nickel-induced hepatotoxicity in rats

    Science.gov (United States)

    Stephen Adeyemi, Oluyomi; Sokolayemji Aroge, Cincin; Adewumi Akanji, Musbau

    2017-01-01

    Multiple health-promoting effects have been attributed to the consumption of Moringa oleifera leaves, as part of diet without adequate scientific credence. This study evaluated the effect of M. oleifera-based diets on nickel (Ni) - induced hepatotoxicity in rats. Male rats assigned into six groups were given oral administration of 20 mg/kg body weight nickel sulfate in normal saline and either fed normal diet orM. oleifera-based diets for 21 days. All animals were sacrificed under anesthesia 24 hours after the last treatment. Ni exposure elevated the rat plasma activities of alanine transaminase, aspartate transaminase and alkaline phosphatase significantly. Ni exposure also raised the levels of triglyceride, total cholesterol and low-density lipoprotein cholesterol while depleting the high-density lipoprotein cholesterol concentration. Further, Ni exposure raised rat plasma malondialdehyde but depleted reduced glutathione concentrations. The histopathological presentations revealed inflammation and cellular degeneration caused by Ni exposure. We show evidence thatM. oleifera-based diets protected against Ni-induced hepatotoxicity by improving the rat liver function indices, lipid profile as well as restoring cellular architecture and integrity. Study lends credence to the health-promoting value ofM. oleifera as well as underscores its potential to attenuate hepatic injury. PMID:28808207

  15. Gemfibrozil disrupts lysophosphatidylcholine and bile acid homeostasis via PPARα and its relevance to hepatotoxicity.

    Science.gov (United States)

    Liu, Aiming; Krausz, Kristopher W; Fang, Zhong-Ze; Brocker, Chad; Qu, Aijuan; Gonzalez, Frank J

    2014-04-01

    Gemfibrozil, a ligand of peroxisome proliferator-activated receptor α (PPARα), is one of the most widely prescribed anti-dyslipidemia fibrate drugs. Among the adverse reactions observed with gemfibrozil are alterations in liver function, cholestatic jaundice, and cholelithiasis. However, the mechanisms underlying these toxicities are poorly understood. In this study, wild-type and Ppara-null mice were dosed with a gemfibrozil-containing diet for 14 days. Ultra-performance chromatography electrospray ionization quadrupole time-of-flight mass spectrometry-based metabolomics and traditional approaches were used to assess the mechanism of gemfibrozil-induced hepatotoxicity. Unsupervised multivariate data analysis revealed four lysophosphatidylcholine components in wild-type mice that varied more dramatically than those in Ppara-null mice. Targeted metabolomics revealed taurocholic acid and tauro-α-muricholic acid/tauro-β-muricholic acid were significantly increased in wild-type mice, but not in Ppara-null mice. In addition to the above perturbations in metabolite homeostasis, phenotypic alterations in the liver were identified. Hepatic genes involved in metabolism and transportation of lysophosphatidylcholine and bile acid compounds were differentially regulated between wild-type and Ppara-null mice, in agreement with the observed downstream metabolic alterations. These data suggest that PPARα mediates gemfibrozil-induced hepatotoxicity in part by disrupting phospholipid and bile acid homeostasis.

  16. Microscale 3D Liver Bioreactor for In Vitro Hepatotoxicity Testing under Perfusion Conditions.

    Science.gov (United States)

    Freyer, Nora; Greuel, Selina; Knöspel, Fanny; Gerstmann, Florian; Storch, Lisa; Damm, Georg; Seehofer, Daniel; Foster Harris, Jennifer; Iyer, Rashi; Schubert, Frank; Zeilinger, Katrin

    2018-03-15

    The accurate prediction of hepatotoxicity demands validated human in vitro models that can close the gap between preclinical animal studies and clinical trials. In this study we investigated the response of primary human liver cells to toxic drug exposure in a perfused microscale 3D liver bioreactor. The cellularized bioreactors were treated with 5, 10, or 30 mM acetaminophen (APAP) used as a reference substance. Lactate production significantly decreased upon treatment with 30 mM APAP ( p < 0.05) and ammonia release significantly increased in bioreactors treated with 10 or 30 mM APAP ( p < 0.0001), indicating APAP-induced dose-dependent toxicity. The release of prostaglandin E2 showed a significant increase at 30 mM APAP ( p < 0.05), suggesting an inflammatory reaction towards enhanced cellular stress. The expression of genes involved in drug metabolism, antioxidant reactions, urea synthesis, and apoptosis was differentially influenced by APAP exposure. Histological examinations revealed that primary human liver cells in untreated control bioreactors were reorganized in tissue-like cell aggregates. These aggregates were partly disintegrated upon APAP treatment, lacking expression of hepatocyte-specific proteins and transporters. In conclusion, our results validate the suitability of the microscale 3D liver bioreactor to detect hepatotoxic effects of drugs in vitro under perfusion conditions.

  17. The use of cultured hepatocytes to investigate the metabolism of drugs and mechanisms of drug hepatotoxicity.

    Science.gov (United States)

    Gómez-Lechón, M J; Ponsoda, X; Bort, R; Castell, J V

    2001-01-01

    Hepatotoxins can be classified as intrinsic when they exert their effects on all individuals in a dose-dependent manner, and as idiosyncratic when their effects are the consequence of an abnormal metabolism of the drug by susceptible individuals (metabolic idiosyncrasy) or of an immune-mediated injury to hepatocytes (allergic hepatitis). Some xenobiotics are electrophilic, and others are biotransformed by the liver into highly reactive metabolites that are usually more toxic than the parent compound. This activation process is the key to many hepatotoxic phenomena. Mitochondria are a frequent target of hepatotoxic drugs, and the alteration of their function has immediate effects on the energy balance of cells (depletion of ATP). Lipid peroxidation, oxidative stress, alteration of Ca(2+) homeostasis, and covalent binding to cell macromolecules are the molecular mechanisms that are frequently involved in the toxicity of xenobiotics. Against these potential hazards, cells have their own defence mechanisms (for example, glutathione, DNA repair, suicide inactivation). Ultimately, toxicity is the balance between bioactivation and detoxification, which determines whether a reactive metabolite elicits a toxic effect. The ultimate goal of in vitro experiments is to generate the type of scientific information needed to identify compounds that are potentially toxic to man. For this purpose, both the design of the experiments and the interpretation of the results are critical.

  18. Protective Effects of Essential Oils as Natural Antioxidants against Hepatotoxicity Induced by Cyclophosphamide in Mice.

    Science.gov (United States)

    Sheweita, Salah A; El-Hosseiny, Lobna S; Nashashibi, Munther A

    2016-01-01

    Clinical application of cyclophosphamide (CP) as an anticancer drug is often limited due to its toxicity. CP is metabolized mainly in the liver by cytochrome P450 system into acrolein which is the proximate toxic metabolite. Many different natural antioxidants were found to alleviate the toxic effects of various toxic agents via different mechanisms. Therefore, the present study aimed at investigating the role of essential oils extracted from fennel, cumin and clove as natural antioxidants in the alleviation of hepatotoxicity induced by CP through assessment of hepatotoxicity biomarkers (AST, ALT, ALP), histopathology of liver tissues as well as other biochemical parameters involved in the metabolism of CP. The data of the present study showed that treatment of male mice with cyclophosphamide (2.5 mg/Kg BW) as repeated dose for 28 consecutive days was found to induce hepatotoxicity through the elevation in the activities of AST, ALT, and ALP. Combined administration of any of these oils with CP to mice partially normalized the altered hepatic biochemical markers caused by CP, whereas administration of fennel, clove or cumin essential oils alone couldn't change liver function indices. Moreover, CP caused histological changes in livers of mice including swelling and dilation in sinusoidal space, inflammation in portal tract and hepatocytes, as well as, hyperplasia in Kuppfer cells. However, co-administration of any of the essential oils with CP alleviated to some extent the changes caused by CP but not as the normal liver. CP was also found to induce free radical levels (measured as thiobarbituric acid reactive substances) and inhibited the activities of superoxide dismutase, glutathione reductase, and catalase as well as activities and protein expressions of both glutathione S-transferase (GSTπ) and glutathione peroxidase. Essential oils restored changes in activities of antioxidant enzymes (SOD, CAT, GR, GST, and GPx) caused by CP to their normal levels compared

  19. Modulatory effects of dietary inclusion of garlic (Allium sativum) on gentamycin-induced hepatotoxicity and oxidative stress in rats.

    Science.gov (United States)

    Ademiluyi, Adedayo O; Oboh, Ganiyu; Owoloye, Tosin R; Agbebi, Oluwaseun J

    2013-06-01

    To investigate the ameliorative effect of dietary inclusion of garlic (Allium sativum) on gentamycin-induced hepatotoxicity in rats. Adult male rats were randomly divided into four groups with six animals in each group. Groups 1 and 2 were fed basal diet while Groups 3 and 4 were fed diets containing 2% and 4% garlic respectively for 27 d prior to gentamycin administration. Hepatotoxicity was induced by the intraperitoneal administration of gentamycin (100 mg/kg body weight) for 3 d. The liver and plasma were studied for hepatotoxicity and antioxidant indices. Gentamycin induces hepatic damage as revealed by significant (P<0.05) elevation of liver damage marker enzymes (aspartate transaminase and alanine aminotransferase) and reduction in plasma albumin level. Gentamycin also caused a significant (P<0.05) alteration in plasma and liver enzymatic (catalase, glutathione and super oxygen dehydrogenises) and non-enzymatic (glutathione and vitamin C) antioxidant indices with concomitant increase in the malondialdehyde content; however, there was a significant (P<0.05) restoration of the antioxidant status coupled with significant (P<0.05) decrease in the tissues' malondialdehyde content, following consumption of diets containing garlic. These results suggest that dietary inclusion of garlic powder could protect against gentamycin-induced hepatotoxicity, improve antioxidant status and modulate oxidative stress; a function attributed to their phenolic constituents.

  20. Precision-cut liver slices as an ex vivo model to study idiosyncratic hepatotoxicity in mouse and human

    NARCIS (Netherlands)

    Hadi, Mackenzie; Chen, Yixi; Emmen, Harry; Stitzinger, Miranda; Groothuis, Genoveva

    Adverse drug reactions (ADRs) related to hepatotoxicity and drug hypersensitivity are responsible for the top two of toxicity-related drug withdrawals and there are no adequate translational strategies to predict safety. Idiosyncratic adverse drug reactions (IADRs) are ADRs that are rare and

  1. Risk assessment of hepatotoxicity among tuberculosis and human immunodeficiency virus/AIDS-coinfected patients under tuberculosis treatment

    Directory of Open Access Journals (Sweden)

    Williams Ngouleun

    2016-01-01

    Conclusion: The results showed that human immunodeficiency virus status and alcohol consumption constitutes aggravating factors for the occurrence of hepatic toxicity. In addition, the consumption of antioxidant foods simultaneously with TB drugs help in reducing the hepatotoxic effects of these drugs.

  2. Relationship Between Structural Alerts in NSAIDs and Idiosyncratic Hepatotoxicity : An Analysis of Spontaneous Report Data from the WHO Database

    NARCIS (Netherlands)

    Jessurun, Naomi; van Puijenbroek, Eugene

    2015-01-01

    BACKGROUND: Idiosyncratic drug reactions such as hepatotoxicity and blood dyscrasias represent one of the major causes of drug withdrawal from the market. According to the reactive metabolite (RM) concept, this may be due to the metabolic activation of structural alerts (SAs), functionalities in the

  3. Integrative cross-omics analysis in primary mouse hepatocytes unravels mechanisms of cyclosporin A-induced hepatotoxicity

    NARCIS (Netherlands)

    Hof, W.F.P.M.; Summeren, van A.; Lommen, A.; Coonen, M.L.J.; Brauers, K.; Herwijnen, van M.; Wodzig, W.K.W.H.; Kleinjans, J.C.S.

    2014-01-01

    The liver is responsible for drug metabolism and drug-induced hepatotoxicity is the most frequent reason for drug withdrawal, indicating that better pre-clinical toxicity tests are needed. In order to bypass animal models for toxicity screening, we exposed primary mouse hepatocytes for exploring the

  4. Hesperidin protects against cyclophosphamide-induced hepatotoxicity by upregulation of PPARγ and abrogation of oxidative stress and inflammation.

    Science.gov (United States)

    Mahmoud, Ayman M

    2014-09-01

    The most important reason for the non-approval and withdrawal of drugs by the Food and Drug Administration is hepatotoxicity. Therefore, this study was undertaken to evaluate the protective effects of hesperidin against cyclophosphamide (CYP)-induced hepatotoxicity in Wistar rats. The rats received a single intraperitoneal dose of CYP of 200 mg/kg body mass, followed by treatment with hesperidin, orally, at doses of 25 and 50 mg/kg for 11 consecutive days. CYP induced hepatic damage, as evidenced by the significantly elevated levels of serum pro-inflammatory cytokines, serum transaminases, liver lipid peroxidation, and nitric oxide. As a consequence, there was reduced glutathione content, and the activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, were markedly reduced. In addition, CYP administration induced a considerable downregulation of peroxisome proliferator activated receptor gamma (PPARγ) and upregulation of nuclear factor-kappa B (NF-κB) and inducible nitric oxide synthase (iNOS) mRNA expression. Hesperidin, in a dose-dependent manner, rejuvenated the altered markers to an almost normal state. In conclusion, hesperidin showed a potent protective effect against CYP-induced oxidative stress and inflammation leading to hepatotoxicity. The study suggests that hesperidin exerts its protective effect against CYP-induced hepatotoxicity through upregulation of hepatic PPARγ expression and abrogation of inflammation and oxidative stress.

  5. Histological and immunohistochemical effects of Curcuma longa on activation of rat hepatic stellate cells after cadmium induced hepatotoxicity.

    Science.gov (United States)

    El-Mansy, A A; Mazroa, S A; Hamed, W S; Yaseen, A H; El-Mohandes, E A

    2016-01-01

    The liver is a target for toxic chemicals such as cadmium (Cd). When the liver is damaged, hepatic stellate cells (HSC) are activated and transformed into myofibroblast-like cells, which are responsible for liver fibrosis. Curcuma longa has been reported to exert a hepato-protective effect under various pathological conditions. We investigated the effects of C. longa administration on HSC activation in response to Cd induced hepatotoxicity. Forty adult male albino rats were divided into: group 1 (control), group 2 (Cd treated), group 3 (C. longa treated) and group 4 (Cd and C. longa treated). After 6 weeks, liver specimens were prepared for light and electron microscopy examination of histological changes and immunohistochemical localization of alpha smooth muscle actin (αSMA) as a specific marker for activated HSC. Activated HSC with a positive αSMA immune reaction were not detected in groups 1 and 3. Large numbers of activated HSC with αSMA immune reactions were observed in group 2 in addition to Cd induced hepatotoxic changes including excess collagen deposition in thickened portal triads, interlobular septa with hepatic lobulation, inflammatory cell infiltration, a significant increase in Kupffer cells and degenerated hepatocytes. In group 4, we observed a significant decrease in HSC that expressed αSMA with amelioration of the hepatotoxic changes. C. longa administration decreased HSC activation and ameliorated hepatotoxic changes caused by Cd in adult rats.

  6. Minocycline hepatotoxicity: Clinical characterization and identification of HLA-B∗35:02 as a risk factor.

    Science.gov (United States)

    Urban, Thomas Jacob; Nicoletti, Paola; Chalasani, Naga; Serrano, José; Stolz, Andrew; Daly, Ann K; Aithal, Guruprasad P; Dillon, John; Navarro, Victor; Odin, Joseph; Barnhart, Huiman; Ostrov, David; Long, Nanye; Cirulli, Elizabeth Trilby; Watkins, Paul Brent; Fontana, Robert John

    2017-07-01

    Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline drug-induced liver injury (DILI) in a well-phenotyped cohort of patients. Caucasian patients with minocycline DILI underwent genome-wide genotyping and were compared to unexposed population controls. Human leukocyte antigen (HLA) binding of minocycline was assessed using AutoDock Vina. Among the 25 cases, 80% were female, median age was 19years and median latency from drug start to DILI onset was 318days. At presentation, 76% had acute hepatocellular liver injury, median ALT 1,077U/L (range: 63 to 2,333), median bilirubin 4.5mg/dl (range: 0.2 to 16.7), and 90% had a +ANA. During follow-up, 50% were treated with corticosteroids and no participants died or required a liver transplant. A significant association was noted between HLA-B∗35:02 and risk for minocycline DILI; a 16% carrier frequency in DILI cases compared to 0.6% in population controls (odds ratio: 29.6, 95% CI: 7.8-89.8, p=2.5×10 -8 ). Verification of HLA-B∗35:02 imputation was confirmed by sequence-based HLA typing. HLA-B∗35:02 carriers had similar presenting features and outcomes compared to non-carriers. In silico modeling studies support the hypothesis that direct binding of minocycline to this novel HLA risk allele might be an important initiating event in minocycline DILI. HLA-B∗35:02 is a rare HLA allele that was more frequently identified in the 25 minocycline DILI cases compared to population controls. If confirmed in other cohorts, this HLA allele may prove to be a useful diagnostic marker of minocycline DILI. Development of liver injury following prolonged use of minocycline for acne is a rare but potentially severe form of drug-induced liver injury. Our study demonstrates that individuals who are HLA-B∗35:02 carriers are at increased risk of developing minocycline related liver injury. These results may

  7. Yogi Detox Tea: A Potential Cause of Acute Liver Failure.

    Science.gov (United States)

    Kesavarapu, Keerthana; Kang, Mitchell; Shin, Jaewook James; Rothstein, Kenneth

    2017-01-01

    We present a case of acute fulminant liver failure from a liver detoxification tea. We present a 60-year-old female with weakness, lethargy, scleral icterus, jaundice, and worsening mental status. She drank herbal tea three times a day for 14 days prior to symptom development. Liver tests were elevated. Remaining laboratory tests and imaging were negative for other etiologies. An ultrasound-guided liver biopsy showed submassive necrosis. A literature search on the ingredients shows six ingredients as having hepatotoxic effects and remaining ingredients as having very sparse hepatoprotective data. Healthcare professionals should discuss herbal medication and tea use and report adverse effects.

  8. Yogi Detox Tea: A Potential Cause of Acute Liver Failure

    Directory of Open Access Journals (Sweden)

    Keerthana Kesavarapu

    2017-01-01

    Full Text Available We present a case of acute fulminant liver failure from a liver detoxification tea. We present a 60-year-old female with weakness, lethargy, scleral icterus, jaundice, and worsening mental status. She drank herbal tea three times a day for 14 days prior to symptom development. Liver tests were elevated. Remaining laboratory tests and imaging were negative for other etiologies. An ultrasound-guided liver biopsy showed submassive necrosis. A literature search on the ingredients shows six ingredients as having hepatotoxic effects and remaining ingredients as having very sparse hepatoprotective data. Healthcare professionals should discuss herbal medication and tea use and report adverse effects.

  9. Mechanism Profiling of Hepatotoxicity Caused by Oxidative Stress Using Antioxidant Response Element Reporter Gene Assay Models and Big Data.

    Science.gov (United States)

    Kim, Marlene Thai; Huang, Ruili; Sedykh, Alexander; Wang, Wenyi; Xia, Menghang; Zhu, Hao

    2016-05-01

    Hepatotoxicity accounts for a substantial number of drugs being withdrawn from the market. Using traditional animal models to detect hepatotoxicity is expensive and time-consuming. Alternative in vitro methods, in particular cell-based high-throughput screening (HTS) studies, have provided the research community with a large amount of data from toxicity assays. Among the various assays used to screen potential toxicants is the antioxidant response element beta lactamase reporter gene assay (ARE-bla), which identifies chemicals that have the potential to induce oxidative stress and was used to test > 10,000 compounds from the Tox21 program. The ARE-bla computational model and HTS data from a big data source (PubChem) were used to profile environmental and pharmaceutical compounds with hepatotoxicity data. Quantitative structure-activity relationship (QSAR) models were developed based on ARE-bla data. The models predicted the potential oxidative stress response for known liver toxicants when no ARE-bla data were available. Liver toxicants were used as probe compounds to search PubChem Bioassay and generate a response profile, which contained thousands of bioassays (> 10 million data points). By ranking the in vitro-in vivo correlations (IVIVCs), the most relevant bioassay(s) related to hepatotoxicity were identified. The liver toxicants profile contained the ARE-bla and relevant PubChem assays. Potential toxicophores for well-known toxicants were created by identifying chemical features that existed only in compounds with high IVIVCs. Profiling chemical IVIVCs created an opportunity to fully explore the source-to-outcome continuum of modern experimental toxicology using cheminformatics approaches and big data sources. Kim MT, Huang R, Sedykh A, Wang W, Xia M, Zhu H. 2016. Mechanism profiling of hepatotoxicity caused by oxidative stress using antioxidant response element reporter gene assay models and big data. Environ Health Perspect 124:634-641;

  10. NMR-based metabonomic analysis of the hepatotoxicity induced by combined exposure to PCBs and TCDD in rats

    International Nuclear Information System (INIS)

    Lu Chunfeng; Wang Yimei; Sheng Zhiguo; Liu Gang; Fu Ze; Zhao Jing; Zhao Jun; Yan Xianzhong; Zhu Benzhan; Peng Shuangqing

    2010-01-01

    A metabonomic approach using 1 H NMR spectroscopy was adopted to investigate the metabonomic pattern of rat urine after oral administration of environmental endocrine disruptors (EDs) polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) alone or in combination and to explore the possible hepatotoxic mechanisms of combined exposure to PCBs and TCDD. 1 H NMR spectra of urines collected 24 h before and after exposure were analyzed via pattern recognition by using principal component analysis (PCA). Serum biochemistry and liver histopathology indicated significant hepatotoxicity in the rats of the combined group. The PCA scores plots of urinary 1 H NMR data showed that all the treatment groups could be easily distinguished from the control group, so could the PCBs or TCDD group and the combined group. The loadings plots of the PCA revealed remarkable increases in the levels of lactate, glucose, taurine, creatine, and 2-hydroxy-isovaleric acid and reductions in the levels of 2-oxoglutarate, citrate, succinate, hippurate, and trimethylamine-N-oxide in rat urine after exposure. These changes were more striking in the combined group. The changed metabolites may be considered possible biomarker for the hepatotoxicity. The present study demonstrates that combined exposure to PCBs and TCDD induced significant hepatotoxicity in rats, and mitochondrial dysfunction and fatty acid metabolism perturbations might contribute to the hepatotoxicity. There was good conformity between changes in the urine metabonomic pattern and those in serum biochemistry and liver histopathology. These results showed that the NMR-based metabonomic approach may provide a promising technique for the evaluation of the combined toxicity of EDs.

  11. Hepatotoxicity associated with sulfasalazine in inflammatory arthritis: A case series from a local surveillance of serious adverse events

    Directory of Open Access Journals (Sweden)

    Rankin Elizabeth

    2008-04-01

    Full Text Available Abstract Background Spontaneous reporting systems for adverse drug reactions (ADRs are handicapped by under-reporting and limited detail on individual cases. We report an investigation from a local surveillance for serious adverse drug reactions associated with disease modifying anti-rheumatic drugs that was triggered by the occurrence of liver failure in two of our patients. Methods Serious ADR reports have been solicited from local clinicians by regular postcards over the past seven years. Patients', who had hepatotoxicity on sulfasalazine and met a definition of a serious ADR, were identified. Two clinicians reviewed structured case reports and assessed causality by consensus and by using a causality assessment instrument. The likely frequency of hepatotoxicity with sulfasalazine was estimated by making a series of conservative assumptions. Results Ten cases were identified: eight occurred during surveillance. Eight patients were hospitalised, two in hepatic failure – one died after a liver transplant. All but one event occurred within 6 weeks of treatment. Seven patients had a skin rash, three eosinophilia and one interstitial nephritis. Five patients were of Black British of African or Caribbean descent. Liver enzymes showed a hepatocellular pattern in four cases and a mixed pattern in six. Drug-related hepatotoxicity was judged probable or highly probable in 8 patients. The likely frequency of serious hepatotoxicity with sulfasalazine was estimated at 0.4% of treated patients. Conclusion Serious hepatotoxicity associated with sulfasalazine appears to be under-appreciated and intensive monitoring and vigilance in the first 6 weeks of treatment is especially important.

  12. Acetaminophen (Paracetamol) induced acute liver failure - A social problem in an era of increasing tendency to self-treatment.

    Science.gov (United States)

    Wróblewski, Tadeusz; Kobryń, Konrad; Kozieł, Sławomir; Ołdakowska-Jedynak, Urszula; Pinkas, Jarosław; Danielewicz, Roman; Ziarkiewicz-Wróblewska, Bogna; Krawczyk, Marek

    2015-01-01

    The widespread availability of medication without prescription, so-called over the counter (OTC), and the rapid development of health consciousness of Poles is associated with broad access to medical information in the mass media. This causes patients to recognize their own disease, cancel doctor's appointments, and begin self-treatment. This time and money-saving behavior, often signaled by pain, usually leads to the treatment of symptoms alone, without seeking the cause of the disease.The aim of the study was to present life-threatening paracetamol poisoning, and the treatment of acute liver failure. In 2002-2014, 35 patients were hospitalized due to acute paracetamol poisoning: 17 female and 18 male patients aged between 17-59 (mean 32.3 years). Patients were treated in the surgical intensive care unit, where their parameters of liver and renal function were continuously monitored. If there was no improvement in the liver function, patients underwent albumin dialysis with the Prometheus system and were qualified for liver transplantation (LTx). 26 patients were treated pharmacologically and 7 out of 9 patients who underwent LTx were dialyzed. Overall, 11 patients had 26 albumin dialysis in total; 4 patients died - 1 post-transplant and 3 pre-transplant. Paracetamol is the cause of many poisonings resulting from the lack of public awareness about toxic interactions with alcohol, and suicide attempts. Acetaminophen-induced acute liver failure concerns a small percentage of patients but can be successfully treated with albumin dialysis, and in extreme cases by liver transplantation.

  13. Effect of goat milk on hepatotoxicity induced by antitubercular drugs in rats

    Directory of Open Access Journals (Sweden)

    Sonam Miglani

    2016-10-01

    Full Text Available Aim of the present study was to assess the hepatoprotective activity of goat milk on antitubercular drug-induced hepatotoxicity in rats. Hepatotoxicity was induced in rats using a combination of isoniazid, rifampicin, and pyrazinamide given orally as a suspension for 30 days. Treatment groups received goat milk along with antitubercular drugs. Liver damage was assessed using biochemical and histological parameters. Administration of goat milk (20 mL/kg along with antitubercular drugs (Group III reversed the levels of serum alanine aminotransferase (82 ± 25.1 vs. 128.8 ± 8.9 units/L and aspartate aminotransferase (174.7 ± 31.5 vs. 296.4 ± 56.4 units/L, p<0.01 compared with antitubercular drug treatment Group II. There was a significant decrease in serum alanine aminotransferase (41.8 ± 4.1 vs. 128.8 ± 8.9 ​ units/L, p<0.01 and aspartate aminotransferase (128.8 ± 8.54 vs. 296.4 ± 56.4 units/L, p<0.001 levels in Group IV (goat milk 40 mL/kg compared with antitubercular drug treatment Group II. Goat milk (20 mL/kg and 40 mL/kg was effective in reversing the rise in malondialdehyde level compared with the antitubercular drug suspension groups (58.5 ± 2 vs. 89.88 ± 2.42 μmol/mL of tissue homogenate, p<0.001 and 69.7 ± 0.78 vs. 89.88 ± 2.42 μmol/mL of tissue homogenate, p<0.001, respectively. Similarly, both doses of milk significantly prevented a fall in superoxide dismutase level (6.23 ± 0.29 vs. 3.1 ± 0.288 units/mL, p<0.001 and 7.8 ± 0.392 vs. 3.1 ± 0.288 units/mL, p<0.001 compared with the group receiving antitubercular drugs alone. Histological examination indicated that goat milk reduced inflammation and necrotic changes in hepatocytes in the treatment groups. The results indicated that goat milk prevented the antitubercular drug-induced hepatotoxicity and is an effective hepatoprotective agent.

  14. Attenuation of N-nitrosodimethylamine induced hepatotoxicity by Operculina turpethum in Swiss Albino mice

    Science.gov (United States)

    Sharma, Veena; Singh, Manu

    2014-01-01

    Objective(s): To appraise the antihepatotoxic efficacy of ethanolic extract of Operculum turpethum root on the liver of Swiss albino mice. Materials and Methods: Hepatic fibrosis was induced in adult male albino mice through intraperitoneal administrations of N-nitrosodimethylamine (NDMA) at the concentration of 10 mg/kg body weight. The liver toxicity and therapeutic effect of the plant ethanolic extract was assessed by the analysis of liver marker enzymes and antioxidant enzymes and liver histopathological studies. Results: Hepatotoxicity was manifested by significantly decreased (PNDMA induced toxicity which was also supported by histopathological studies of the liver. Conclusion: O. turpethum manifested therapeutic effects by significantly restoring the enzymatic levels and reducing the hepatic damage in mice. This work intends to aid researchers in the study of natural products which could be useful in the treatment of liver diseases including cancer. PMID:24592311

  15. Schisandra sphenanthera extract (Wuzhi Tablet protects against chronic-binge and acute alcohol-induced liver injury by regulating the NRF2-ARE pathway in mice

    Directory of Open Access Journals (Sweden)

    Xuezhen Zeng

    2017-09-01

    Full Text Available Alcohol abuse leads to alcoholic liver disease and no effective therapy is currently available. Wuzhi Tablet (WZ, a preparation of extract from Schisandra sphenanthera that is a traditional hepato-protective herb, exerted a significant protective effect against acetaminophen-induced liver injury in our recent studies, but whether WZ can alleviate alcohol-induced toxicity remains unclear. This study aimed to investigate the contribution of WZ to alcohol-induced liver injury by using chronic-binge and acute models of alcohol feeding. The activities of ALT and AST in serum were assessed as well as the level of GSH and the activity of SOD in the liver. The expression of CYP2E1 and proteins in the NRF2-ARE signaling pathway including NRF2, GCLC, GCLM, HO-1 were measured, and the effect of WZ on NRF2 transcriptional activity was determined. We found that both models resulted in liver steatosis accompanied by increased transaminase activities, but that liver injury was significantly attenuated by WZ. WZ administration also inhibited CYP2E1 expression induced by alcohol, and elevated the level of GSH and the activity of SOD in the liver. Moreover, the NRF2-ARE signaling pathway was activated by WZ and the target genes were all upregulated. Furthermore, WZ significantly activated NRF2 transcriptional activity. Collectively, our study demonstrates that WZ protected against alcohol-induced liver injury by reducing oxidative stress and improving antioxidant defense, possibly by activating the NRF2-ARE pathway.

  16. Characterizing the mechanism of thiazolidinedione-induced hepatotoxicity: An in vitro model in mitochondria

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Dan; Wu, Chun-qi [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China); Li, Ze-jun [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China); Guang Dong Pharmaceutical University, Guangzhou 510006 (China); Liu, Yue; Fan, Xing [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China); Wang, Quan-jun, E-mail: wangquanjunbeijing@163.com [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China); Ding, Ri-gao, E-mail: dingrigao@nic.bmi.ac.cn [State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850 (China)

    2015-04-15

    Objective: To characterize the mechanism of action of thiazolidinedione (TZD)-induced liver mitochondrial toxicity caused by troglitazone, rosiglitazone, and pioglitazone in HepaRG cells. Methods: Human hepatoma cells (HepaRG) were treated with troglitazone, rosiglitazone, or pioglitazone (12.5, 25, and 50 μM) for 48 h. The Seahorse Biosciences XF24 Flux Analyzer was used to measure mitochondrial oxygen consumption. The effect of TZDs on reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. The mitochondrial ultrastructure of HepaRG cells was observed under a transmission electrical microscope (TEM). mtDNA content was evaluated by real-time PCR, and ATP content and mitochondrial respiratory chain (MRC) complex I, II, III, IV activity were measured via chemiluminescence. Results were considered statistically significant at p < 0.05. Results: Among the three drugs, troglitazone exhibited the highest potency, followed by rosiglitazone, and then pioglitazone. The TZDs caused varying degrees of mitochondrial respiratory function disorders including decreases in oxygen consumption, MRC activity, and ATP level, and an elevation in ROS level. TZD treatment resulted in mtDNA content decline, reduction in MMP, and alterations of mitochondrial structure. Conclusion: All investigated TZDs show a certain degree of mitochondrial toxicity, with troglitazone exhibiting the highest potency. The underlying mechanism of TZD-induced hepatotoxicity may be associated with alterations in mitochondrial respiratory function disorders, oxidative stress, and changes in membrane permeability. These parameters may be used early in drug development to further optimize risk:benefit profiles. - Highlights: • We compared three TZD mitochondrial toxicity characteristics in HepaRG cells. • TZD induced respiratory disorders and mitochondrial structural damage. • Mitochondrial toxicity evaluation presents guidance value for hepatotoxicity.

  17. Hepatotoxicity induced by horse ATG and reversed by rabbit ATG: a case report

    Directory of Open Access Journals (Sweden)

    Al-Anazi Khalid A

    2007-06-01

    Full Text Available Abstract Background The use of antilymphocyte agents has improved patient and graft survival in hematopoietic stem cell and solid organ transplantation but has been associated with the development of short-term toxicities as well as long-term complications. Case presentation We report a young female with Fanconi anemia who received antithymocyte globulin as part of the conditioning regimen prior to her planned allogeneic hematopoietic stem cell transplant at King Faisal Specialist Hospital and Research Centre in Riyadh. She developed sudden and severe hepatotoxicity after receiving the first dose of horse antithymocyte globulin, manifested by marked elevation of serum transaminases and mild elevation of serum bilirubin level. Immediately after withdrawal of the offending agent and shifting to the rabbit form of antithymocyte globulin, the gross liver dysfunction started to subside and the hepatic profile results returned to the pre-transplant levels few weeks later. The patient had her allogeneic hematopoietic stem cell transplant as planned without any further hepatic complications. After having a successful allograft, she was discharged from the stem cell transplant unit. During her follow up at the outpatient clinic, the patient remained very well and no major complication was encountered. Conclusion Hepatotoxicity related to the utilization of antithymocyte globulin varies considerably in severity and may be transient or long standing. There may be individual or population based susceptibilities to the development of side effects and these adverse reactions may also vary with the choice of the agent used. Encountering adverse effects with one type of antithymocyte agents should not discourage clinicians from shifting to another type in situations where continuation of the drug is vital.

  18. Characterizing the mechanism of thiazolidinedione-induced hepatotoxicity: An in vitro model in mitochondria

    International Nuclear Information System (INIS)

    Hu, Dan; Wu, Chun-qi; Li, Ze-jun; Liu, Yue; Fan, Xing; Wang, Quan-jun; Ding, Ri-gao

    2015-01-01

    Objective: To characterize the mechanism of action of thiazolidinedione (TZD)-induced liver mitochondrial toxicity caused by troglitazone, rosiglitazone, and pioglitazone in HepaRG cells. Methods: Human hepatoma cells (HepaRG) were treated with troglitazone, rosiglitazone, or pioglitazone (12.5, 25, and 50 μM) for 48 h. The Seahorse Biosciences XF24 Flux Analyzer was used to measure mitochondrial oxygen consumption. The effect of TZDs on reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. The mitochondrial ultrastructure of HepaRG cells was observed under a transmission electrical microscope (TEM). mtDNA content was evaluated by real-time PCR, and ATP content and mitochondrial respiratory chain (MRC) complex I, II, III, IV activity were measured via chemiluminescence. Results were considered statistically significant at p < 0.05. Results: Among the three drugs, troglitazone exhibited the highest potency, followed by rosiglitazone, and then pioglitazone. The TZDs caused varying degrees of mitochondrial respiratory function disorders including decreases in oxygen consumption, MRC activity, and ATP level, and an elevation in ROS level. TZD treatment resulted in mtDNA content decline, reduction in MMP, and alterations of mitochondrial structure. Conclusion: All investigated TZDs show a certain degree of mitochondrial toxicity, with troglitazone exhibiting the highest potency. The underlying mechanism of TZD-induced hepatotoxicity may be associated with alterations in mitochondrial respiratory function disorders, oxidative stress, and changes in membrane permeability. These parameters may be used early in drug development to further optimize risk:benefit profiles. - Highlights: • We compared three TZD mitochondrial toxicity characteristics in HepaRG cells. • TZD induced respiratory disorders and mitochondrial structural damage. • Mitochondrial toxicity evaluation presents guidance value for hepatotoxicity

  19. Modulatory Effect of Methanol Extract of Piper guineense in CCl₄-Induced Hepatotoxicity in Male Rats.

    Science.gov (United States)

    Oyinloye, Babatunji Emmanuel; Osunsanmi, Foluso Oluwagbemiga; Ajiboye, Basiru Olaitan; Ojo, Oluwafemi Adeleke; Kappo, Abidemi Paul

    2017-08-24

    This study seeks to investigate the possible protective role of the methanol extract of Piper guineense seeds against CCl₄-induced hepatotoxicity in an animal model. Hepatotoxicity was induced by administering oral doses of CCl₄ (1.2 g/kg bw) three times a week for three weeks. Group 1 (Control) and Group 2 (CCl₄) were left untreated; Piper guineense (PG; 400 mg/kg bw) was administered to Group 3 (T₁) by oral gavage for 14 days prior to the administration of CCl₄ and simultaneously with CCl₄; PG (400 mg/kg bw) was administered simultaneously with CCl₄ in Group 4 (T₂); and Livolin forte (20 mg/kg bw) was administered simultaneously with CCl₄ in Group 5 (T₃), the standard drug group. The administration of CCl₄ induces histopathological alteration in the liver, with concomitant increased activities of serum hepatic marker enzymes associated with increased levels of lipid peroxidation. Similarly, there was decrease in non-enzymatic (reduced glutathione) and enzymatic antioxidants (glutathione S-transferase), superoxide dismutase, and catalase. An elevation in serum triglyceride and total cholesterol levels was noticed along with decreased levels of serum total protein. Treatment with PG 400 mg/kg bw exhibited excellent modulatory activity with respect to the different parameters studied by reversing all the above-mentioned biochemical changes significantly in the experimental animals. These results suggest that PG offered protection comparable to that of Livolin forte with better efficacy when pre-treated with 400 mg/kg bw 14 days prior to CCl₄-exposure.

  20. Role of ascorbic acid supplement in reducing oxidative stress and hepatotoxicity in lead intoxication

    International Nuclear Information System (INIS)

    Farooq, Y.; Hussain, M.M.; Aleem, S.B.

    2013-01-01

    Objective: The present study was conducted to measure the oxidative stress and hepatotoxicity in lead intoxicated sprague dawley rats with and without supplementation of ascorbic acid. Study Design: Randomized Control Trial. Place of Study: Physiology Department, Army Medical College, Rawalpindi. (From Oct 2007 to Sep 2008) Material and Methods: One hundred and five male rats (age, 90-120 days; weight 200 - 250 gm) were divided into three groups each having 35 rats. Rats of group 1 and group 2 were given weekly injections of sodium acetate (10 mg /kg body weight) and lead acetate (10 mg /kg body weight) respectively, whereas rats of group 3 were administered lead acetate(10 mg /kg body weight) through weekly injections and ascorbic acid in drinking water (500 mg/l). After 6 weeks, 4 ml of blood was drawn from each rat by cardiac puncture. The blood was allowed to clot and serum was separated for estimation of serum malondialdehyde (MDA) levels on spectrophotometer; and serum alanine aminotransferase (ALT) levels and aspartate aminotransferase (AST) levels on Merck Micorlab 200. Results: Lead intoxication of rats revealed that serum MDA levels were raised to 7.8 +- 0.48 micro mol/l (control, 3.2 +-0.39 micro mol/l), ALT levels to 76.26 +- 5.88 IU/l (control, 44.1 +- 3.26) and AST levels to 258.06 +- 13.30 IU/l (control, 156.2 +- 4.97). Ascorbic acid supplementation significantly lowered serum MDA levels (3.8 +- 0.34 micro mol/l), ALT levels (52.26 +-4.57 IU/l) and AST levels (188.13 +- 12.91 IU/l). Conclusion: Ascorbic acid supplementation ameliorates lead intoxication probably by reducing the oxidative stress, thus preventing the development of hepatotoxicity, but this amelioration is not equal to the control. (author)

  1. Blockade of store-operated calcium entry alleviates ethanol-induced hepatotoxicity via inhibiting apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Cui, Ruibing [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China); Yan, Lihui [Shandong Normal University, Jinan, Shandong Province 250012 (China); Luo, Zheng; Guo, Xiaolan [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China); Yan, Ming, E-mail: ymylh@163.com [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China)

    2015-08-15

    Extracellular Ca{sup 2+} influx has been suggested to play a role in ethanol-induced hepatocyte apoptosis and necrosis. Previous studies indicated that store-operated Ca{sup 2+} entry (SOCE) was involved in liver injury induced by ethanol in HepG2 cells. However, the mechanisms underlying liver injury caused by SOCE remain unclear. We aimed to investigate the effects and mechanism of SOCE inhibition on liver injury induced by ethanol in BRL cells and Sprague–Dawley rats. Our data demonstrated that ethanol (0–400 mM) dose-dependently increased hepatocyte injury and 100 mM ethanol significantly upregulated the mRNA and protein expression of SOC for at least 72 h in BRL cells. Blockade of SOCE by pharmacological inhibitors and sh-RNA knockdown of STIM1 and Orai1 attenuated intracellular Ca{sup 2+} overload, restored the mitochondrial membrane potential (MMP), decreased cytochrome C release and inhibited ethanol-induced apoptosis. STIM1 and Orai1 expression was greater in ethanol-treated than control rats, and the SOCE inhibitor corosolic acid ameliorated the histopathological findings and alanine transaminase and aspartate transaminase activity as well as decreased cytochrome C release and inhibited alcohol-induced cell apoptosis. These findings suggest that SOCE blockade could alleviate alcohol-induced hepatotoxicity via inhibiting apoptosis. SOCE might be a useful therapeutic target in alcoholic liver diseases. - Highlights: • Blockade of SOCE alleviated overload of Ca{sup 2+} and hepatotoxicity after ethanol application. • Blockade of SOCE inhibited mitochondrial apoptosis after ethanol application. • SOCE might be a useful therapeutic target in alcoholic liver diseases.

  2. Hospitalized pediatric antituberculosis drug induced hepatotoxicity: Experience of an Indonesian referral hospital

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    Heda Melinda Nataprawira

    2017-05-01

    Full Text Available Objective: To determine the characteristics and risk factors of pediatric antituberculosis drug induced hepatotoxicity (ADIH in Dr. Hasan Sadikin Hospital, a referral hospital in West Java, Indonesia. Methods: Medical records of hospitalized pediatric ADIH from October 2010 to October 2015 were reviewed retrospectively through computer-based search. Descriptive data were presented as percentage. Analytical case-control study on characteristics of ADIH was conducted using Chi-square and Mann Whitney test. Results: Fifty (3.5% out of 1 424 pediatric TB patients developed ADIH; 20 (40% were boys and 30 (60% girls. More than half were under 5 years old and 33 (66% were malnourished. ADIH occured in 29 (58% cases treated for pulmonary TB, 15 (30% for extrapulmonary TB and 6 (12% for both; 34 cases (68% occured during the intensive phase. We identified hepatic comorbidities including CMV infection [1 (2%] and typhoid [1 (2%], and other diseases treated by hepatotoxic drugs such as chemotherapeutic drugs, antiepileptics, and antiretroviral drugs [9 (18%]. Case-control analysis of 50 ADIH cases and 100 TB controls without ADIH showed that the correlation between gender, age, type of TB, nutritional status and comorbidities to occurence of ADIH was statistically insignificant (P = 0.26, 0.765, 0.495, 0.534 9 and 0.336, respectively. Pediatric ADIH was treated using modified British Thoracic Society guidelines. Conclusions: Pediatric ADIH in our hospital is quite frequent, thus identifying risk factors and development of pediatric guideline is mandatory. Further study is needed to identify other risk factors such as genetic acetylator status.

  3. Immunosuppression, hepatotoxicity and depression of antioxidant status by arecoline in albino mice

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    Dasgupta, Romi [Department of Zoology, University of Calcutta, 35 Ballygunge Circular Road, Calcutta 700 019 (India); Saha, Indraneel [Department of Zoology, University of Calcutta, 35 Ballygunge Circular Road, Calcutta 700 019 (India); Pal, Suman [Microbiology Laboratory, Bose Institute, Kankurgachi, Calcutta 700 054 (India); Bhattacharyya, Arindam [Microbiology Laboratory, Bose Institute, Kankurgachi, Calcutta 700 054 (India); Sa, Gaurisankar [Microbiology Laboratory, Bose Institute, Kankurgachi, Calcutta 700 054 (India); Nag, Tapas C [Department of Anatomy, All India Institute of Medical Sciences, New Delhi 110 020 (India); Das, Tania [Microbiology Laboratory, Bose Institute, Kankurgachi, Calcutta 700 054 (India); Maiti, B R [Department of Zoology, University of Calcutta, 35 Ballygunge Circular Road, Calcutta 700 019 (India)

    2006-10-03

    Background: There are about 600 million betel quid chewers in the world. Betal quid chewing is one of the major risk factors of hepatocarcinoma, oropharyngeal and esophagus cancers. Arecoline, the main Areca alkaloid of the betel nut is reported to have cytotoxic, genotoxic and mutagenic effects in various cells. It shows strong correlation to the incidence of oral submucosal fibrosis, leukoplakia and oral cancer, and has also been found to impose toxic manifestations in immune, hepatic and other defense systems of the recipient. Aim: The precise molecular mechanisms underlying the toxic effects of arecoline deserve investigation. To clarify the action of arecoline on defense systems, immune, hepatic and detoxification system were studied in mice. Method: Cell count and cell cycle of the splenocytes were studied for evaluating cell immunity. Liver function test (LFT) was followed by assaying different enzyme systems from serum (SGPT, SGOT and ALP) and liver (GST for detoxication enzyme, SOD and catalase for antioxidant enzymes and GSH for non-enzymatic antioxidant) and by ultrastructural studies of hepatocytes. Results: Here we report that arecoline arrested splenic lymphocyte cell cycle at lower concentration with induced apoptosis at higher concentration thereby causing immunosuppression in arecoline recipients. Besides, it resulted in hepatotoxicity in arecoline recipient mice by disrupting the hepatocyte ultrastructure, as judged by liver ultrastructural studies that showed decreased nuclear size, RER with profusely inflated cysternae and abundance of lipid droplets, and by up regulating hepatotoxic marker enzymes (SGOT and SGPT) in serum. Arecoline also caused depression of antioxidants, i.e., superoxide dismutase (SOD), catalase, reduced glutathione (GSH) and glutathione-S-transferase (GST) that are known to neutralize reactive oxygen species. Conclusion: All these above-mentioned results led us to conclude that arecoline attacks multiple targets to finally

  4. Immunosuppression, hepatotoxicity and depression of antioxidant status by arecoline in albino mice

    International Nuclear Information System (INIS)

    Dasgupta, Romi; Saha, Indraneel; Pal, Suman; Bhattacharyya, Arindam; Sa, Gaurisankar; Nag, Tapas C.; Das, Tania; Maiti, B.R.

    2006-01-01

    Background: There are about 600 million betel quid chewers in the world. Betal quid chewing is one of the major risk factors of hepatocarcinoma, oropharyngeal and esophagus cancers. Arecoline, the main Areca alkaloid of the betel nut is reported to have cytotoxic, genotoxic and mutagenic effects in various cells. It shows strong correlation to the incidence of oral submucosal fibrosis, leukoplakia and oral cancer, and has also been found to impose toxic manifestations in immune, hepatic and other defense systems of the recipient. Aim: The precise molecular mechanisms underlying the toxic effects of arecoline deserve investigation. To clarify the action of arecoline on defense systems, immune, hepatic and detoxification system were studied in mice. Method: Cell count and cell cycle of the splenocytes were studied for evaluating cell immunity. Liver function test (LFT) was followed by assaying different enzyme systems from serum (SGPT, SGOT and ALP) and liver (GST for detoxication enzyme, SOD and catalase for antioxidant enzymes and GSH for non-enzymatic antioxidant) and by ultrastructural studies of hepatocytes. Results: Here we report that arecoline arrested splenic lymphocyte cell cycle at lower concentration with induced apoptosis at higher concentration thereby causing immunosuppression in arecoline recipients. Besides, it resulted in hepatotoxicity in arecoline recipient mice by disrupting the hepatocyte ultrastructure, as judged by liver ultrastructural studies that showed decreased nuclear size, RER with profusely inflated cysternae and abundance of lipid droplets, and by up regulating hepatotoxic marker enzymes (SGOT and SGPT) in serum. Arecoline also caused depression of antioxidants, i.e., superoxide dismutase (SOD), catalase, reduced glutathione (GSH) and glutathione-S-transferase (GST) that are known to neutralize reactive oxygen species. Conclusion: All these above-mentioned results led us to conclude that arecoline attacks multiple targets to finally

  5. Deltamethrin-Induced Hepatotoxicity and Virgin Olive Oil Consumption: An Experimental Study

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    Ali Reza Khalatbary

    2017-11-01

    Full Text Available Background: Deltamethrin (DM is a synthetic pyrethroid insecticide which can lead to pathological effects in mammals through oxidative stress. On the other hand, virgin olive oil (VOO is a rich source of phenolic compounds with antioxidants. The aim of the present study was to determine the protective effects of VOO against DM-induced hepatotoxicity. Methods: Thirty-six mice were randomly separated into 4 groups: vehicle group, VOO group, DM group, and DM plus VOO group. Immunohistochemistry of PARP, COX-2, and caspase-3 with the biochemical analysis of malondialdehyde and total antioxidant capacity levels were performed in the liver samples 5 weeks after gavaging. Statistical analysis was performed using SPSS, version 15. The data were compared between the groups using the Tukey multiple comparison tests and the analysis of the variance. A P value <0.05 was considered significant. Results: The malondialdehyde level in the liver was increased in the DM group (71.18±0.01, whereas it was significantly (P=0.001 decreased after VOO administration in the DM plus VOO group (39.59±2.43. While the total antioxidant capacity level in the liver was decreased in the DM group (3.05±0.05, it was significantly increased (P=0.03 after VOO administration in the DM plus VOO group (3.95±0.04. A greater expression of caspase-3 (P=0.008, COX-2 (P =0.004, and PARP (P 0.006 could be detected in the DM group, while it was significantly (P=0.009 attenuated in the DM plus VOO group. Also, the degeneration of hepatocytes, which was detected in the DM group, was attenuated after VOO consumption. Conclusions: VOO exerted protective effects against DM-induced hepatotoxicity, which might be associated with its anti-apoptotic, anti-inflammatory, and antioxidative properties.

  6. Deltamethrin-Induced Hepatotoxicity and Virgin Olive Oil Consumption: An Experimental Study.

    Science.gov (United States)

    Khalatbary, Ali Reza; Ghabaee, Davood Nasiry Zarrin; Ahmadvand, Hassan; Amiri, Fereshteh Talebpour; Lehi, Somaieh Tadayoni

    2017-11-01

    Deltamethrin (DM) is a synthetic pyrethroid insecticide which can lead to pathological effects in mammals through oxidative stress. On the other hand, virgin olive oil (VOO) is a rich source of phenolic compounds with antioxidants. The aim of the present study was to determine the protective effects of VOO against DM-induced hepatotoxicity. Thirty-six mice were randomly separated into 4 groups: vehicle group, VOO group, DM group, and DM plus VOO group. Immunohistochemistry of PARP, COX-2, and caspase-3 with the biochemical analysis of malondialdehyde and total antioxidant capacity levels were performed in the liver samples 5 weeks after gavaging. Statistical analysis was performed using SPSS, version 15. The data were compared between the groups using the Tukey multiple comparison tests and the analysis of the variance. A P value group (71.18±0.01), whereas it was significantly (P=0.001) decreased after VOO administration in the DM plus VOO group (39.59±2.43). While the total antioxidant capacity level in the liver was decreased in the DM group (3.05±0.05), it was significantly increased (P=0.03) after VOO administration in the DM plus VOO group (3.95±0.04). A greater expression of caspase-3 (P=0.008), COX-2 (P =0.004), and PARP (P 0.006) could be detected in the DM group, while it was significantly (P=0.009) attenuated in the DM plus VOO group. Also, the degeneration of hepatocytes, which was detected in the DM group, was attenuated after VOO consumption. VOO exerted protective effects against DM-induced hepatotoxicity, which might be associated with its anti-apoptotic, anti-inflammatory, and antioxidative properties.

  7. Serum microRNA signatures as "liquid biopsies" for interrogating hepatotoxic mechanisms and liver pathogenesis in human.

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    Julian Krauskopf

    Full Text Available MicroRNAs (miRNAs released into the peripheral circulation upon cellular injury have shown a promise as a new class of tissue-specific biomarkers. We were first to demonstrate that next-generation sequencing analysis of serum from human subjects with acetaminophen-induced liver injury revealed a specific signature of circulating miRNAs. We consequently hypothesized that different types of hepatic liver impairments might feature distinct signatures of circulating miRNAs and that this approach might be useful as minimally invasive diagnostic "liquid biopsies" enabling the interrogation of underlying molecular mechanisms of injury in distant tissues. Therefore we examined serum circulating miRNAs in a total of 72 serum samples from a group of 53 subjects that included patients with accidental acetaminophen overdose, hepatitis B infection, liver cirrhosis and type 2 diabetes as well as gender- and age-matched healthy subjects with no evidence of liver disease. The miRNA signatures were identified using next-generation sequencing that provided analysis for the whole miRNome, including miRNA isoforms. Compared to the healthy subjects, a total of 179 miRNAs showed altered serum levels across the diseased subjects. Although many subjects have elevated alanine aminotransferase suggesting liver impairments, we identified distinct miRNA signatures for different impairments with minimum overlap. Furthermore, the bioinformatics analysis of miRNA signatures revealed relevant molecular pathways associated with the mechanisms of toxicity and or pathogenesis of disease. Interestingly, the high proportion of miRNA isoforms present in the respective signatures indicated a new level of complexity in cellular response to stress or disease. Our study demonstrates for the first time that signatures of circulating miRNAs show specificity for liver injury phenotypes and, once validated, might become useful for diagnosis of organ pathologies as "liquid biopsies".

  8. Serum microRNA signatures as "liquid biopsies" for interrogating hepatotoxic mechanisms and liver pathogenesis in human.

    Science.gov (United States)

    Krauskopf, Julian; de Kok, Theo M; Schomaker, Shelli J; Gosink, Mark; Burt, Deborah A; Chandler, Patricia; Warner, Roscoe L; Johnson, Kent J; Caiment, Florian; Kleinjans, Jos C; Aubrecht, Jiri

    2017-01-01

    MicroRNAs (miRNAs) released into the peripheral circulation upon cellular injury have shown a promise as a new class of tissue-specific biomarkers. We were first to demonstrate that next-generation sequencing analysis of serum from human subjects with acetaminophen-induced liver injury revealed a specific signature of circulating miRNAs. We consequently hypothesized that different types of hepatic liver impairments might feature distinct signatures of circulating miRNAs and that this approach might be useful as minimally invasive diagnostic "liquid biopsies" enabling the interrogation of underlying molecular mechanisms of injury in distant tissues. Therefore we examined serum circulating miRNAs in a total of 72 serum samples from a group of 53 subjects that included patients with accidental acetaminophen overdose, hepatitis B infection, liver cirrhosis and type 2 diabetes as well as gender- and age-matched healthy subjects with no evidence of liver disease. The miRNA signatures were identified using next-generation sequencing that provided analysis for the whole miRNome, including miRNA isoforms. Compared to the healthy subjects, a total of 179 miRNAs showed altered serum levels across the diseased subjects. Although many subjects have elevated alanine aminotransferase suggesting liver impairments, we identified distinct miRNA signatures for different impairments with minimum overlap. Furthermore, the bioinformatics analysis of miRNA signatures revealed relevant molecular pathways associated with the mechanisms of toxicity and or pathogenesis of disease. Interestingly, the high proportion of miRNA isoforms present in the respective signatures indicated a new level of complexity in cellular response to stress or disease. Our study demonstrates for the first time that signatures of circulating miRNAs show specificity for liver injury phenotypes and, once validated, might become useful for diagnosis of organ pathologies as "liquid biopsies".

  9. Incidence of antituberculosis-drug-induced hepatotoxicity and associated risk factors among tuberculosis patients in Dawro Zone, South Ethiopia: A cohort study

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    Wondwossen Abera

    2016-01-01

    Conclusion: The incidence of anti-TB-DIH in Dawro Zone was high. The drug responsible for the hepatotoxicity was not known. However, chronic high alcohol intake was associated with the development of anti-TB-DIH.

  10. Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity

    International Nuclear Information System (INIS)

    Cosgrove, Benjamin D.; King, Bracken M.; Hasan, Maya A.; Alexopoulos, Leonidas G.; Farazi, Paraskevi A.; Hendriks, Bart S.; Griffith, Linda G.; Sorger, Peter K.; Tidor, Bruce; Xu, Jinghai J.

    2009-01-01

    Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce an inflammatory background have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs. However, the low-throughput nature of these models renders them problematic for employment as preclinical screening assays. Here, we present an analogous, but high-throughput, in vitro approach in which drugs are administered to a variety of cell types (primary human and rat hepatocytes and the human HepG2 cell line) across a landscape of inflammatory contexts containing LPS and cytokines TNF, IFNγ, IL-1α, and IL-6. Using this assay, we observed drug-cytokine hepatotoxicity synergies for multiple idiosyncratic hepatotoxicants (ranitidine, trovafloxacin, nefazodone, nimesulide, clarithromycin, and telithromycin) but not for their corresponding non-toxic control compounds (famotidine, levofloxacin, buspirone, and aspirin). A larger compendium of drug-cytokine mix hepatotoxicity data demonstrated that hepatotoxicity synergies were largely potentiated by TNF, IL-1α, and LPS within the context of multi-cytokine mixes. Then, we screened 90 drugs for cytokine synergy in human hepatocytes and found that a significantly larger fraction of the idiosyncratic hepatotoxicants (19%) synergized with a single cytokine mix than did the non-hepatotoxic drugs (3%). Finally, we used an information theoretic approach to ascertain especially informative subsets of cytokine treatments for most highly effective construction of regression models for drug- and cytokine mix-induced hepatotoxicities across these cell systems. Our results suggest that this drug-cytokine co-treatment approach could provide a useful preclinical tool for investigating inflammation-associated idiosyncratic drug hepatotoxicity.

  11. Synthesis and Biological Evaluation of Benzochromenopyrimidinones as Cholinesterase Inhibitors and Potent Antioxidant, Non-Hepatotoxic Agents for Alzheimer’s Disease

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    Youssef Dgachi

    2016-05-01

    Full Text Available We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM, good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.

  12. Imidazopyranotacrines as Non-Hepatotoxic, Selective Acetylcholinesterase Inhibitors, and Antioxidant Agents for Alzheimer′s Disease Therapy

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    Houssem Boulebd

    2016-03-01

    Full Text Available Herein we describe the synthesis and in vitro biological evaluation of thirteen new, racemic, diversely functionalized imidazo pyranotacrines as non-hepatotoxic, multipotent tacrine analogues. Among these compounds, 1-(5-amino-2-methyl-4-(1-methyl-1H-imidazol-2-yl-6,7,8,9-tetrahydro-4H-pyrano[2,3-b]quinolin-3-ylethan-1-one (4 is non-hepatotoxic (cell viability assay on HepG2 cells, a selective but moderately potent EeAChE inhibitor (IC50 = 38.7 ± 1.7 μM, and a very potent antioxidant agent on the basis of the ORAC test (2.31 ± 0.29 μmol·Trolox/μmol compound.

  13. Gene expression profiling in the liver of CD-1 mice to characterize the hepatotoxicity of triazole fungicides

    International Nuclear Information System (INIS)

    Goetz, Amber K.; Bao, Wenjun; Ren, Hongzu; Schmid, Judith E.; Tully, Douglas B.; Wood, Carmen; Rockett, John C.; Narotsky, Michael G.; Sun, Guobin; Lambert, Guy R.; Thai, S.-F.; Wolf, Douglas C.; Nesnow, Stephen; Dix, David J.

    2006-01-01

    Four triazole fungicides used in agricultural or pharmaceutical applications were examined for hepatotoxic effects in mouse liver. Besides organ weight, histopathology, and cytochrome P450 (CYP) enzyme induction, DNA microarrays were used to generate gene expression profiles and hypotheses on potential mechanisms of action for this class of chemicals. Adult male CD-1 mice were exposed daily for 14 days to fluconazole, myclobutanil, propiconazole, or triadimefon at three dose levels by oral gavage. Doses were based on previous studies that resulted in liver hypertrophy or hepatotoxicity. All four triazoles caused hepatocyte hypertrophy, and all except triadimefon increased relative liver/body weight ratios at the middle and high dose levels. CYP enzyme activities were also induced by all four triazoles at the middle and high doses as measured by the dealkylations of four alkoxyresorufins, although some differences in substrate specificity were observed. Consistent with this common histopathology and biochemistry, several CYP and xenobiotic metabolizing enzyme (XME) genes were differentially expressed in response to all four (Cyp2d26 and Cyp3a11), or three of the four (Cyp2c40, Cyp2c55, Ces2, Slco1a4) triazoles. Differential expression of numerous other CYP and XME genes discriminated between the various triazoles, consistent with differences in CYP enzyme activities, and indicative of possible differences in mechanisms of hepatotoxicity or dose response. Multiple isoforms of Cyp1a, 2b, 2c, 3a, and other CYP and XME genes regulated by the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) were differentially expressed following triazole exposure. Based on these results, we expanded on our original hypothesis that triazole hepatotoxicity was mediated by CYP induction, to include additional XME genes, many of which are modulated by CAR and PXR

  14. High Dose Atorvastatin Associated with Increased Risk of Significant Hepatotoxicity in Comparison to Simvastatin in UK GPRD Cohort.

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    Alan T Clarke

    Full Text Available Occasional risk of serious liver dysfunction and autoimmune hepatitis during atorvastatin therapy has been reported. We compared the risk of hepatotoxicity in atorvastatin relative to simvastatin treatment.The UK GPRD identified patients with a first prescription for simvastatin [164,407] or atorvastatin [76,411] between 1997 and 2006, but with no prior record of liver disease, alcohol-related diagnosis, or liver dysfunction. Incident liver dysfunction in the following six months was identified by biochemical value and compared between statin groups by Cox regression model adjusting for age, sex, year treatment started, dose, alcohol consumption, smoking, body mass index and comorbid conditions.Moderate to severe hepatotoxicity [bilirubin >60μmol/L, AST or ALT >200U/L or alkaline phosphatase >1200U/L] developed in 71 patients on atorvastatin versus 101 on simvastatin. Adjusted hazard ratio [AHR] for all atorvastatin relative to simvastatin was 1.9 [95% confidence interval 1.4-2.6]. High dose was classified as 40-80mg daily and low dose 10-20mg daily. Hepatotoxicity occurred in 0.44% of 4075 patients on high dose atorvastatin [HDA], 0.07% of 72,336 on low dose atorvastatin [LDA], 0.09% of 44,675 on high dose simvastatin [HDS] and 0.05% of 119,732 on low dose simvastatin [LDS]. AHRs compared to LDS were 7.3 [4.2-12.7] for HDA, 1.4 [0.9-2.0] for LDA and 1.5 [1.0-2.2] for HDS.The risk of hepatotoxicity was increased in the first six months of atorvastatin compared to simvastatin treatment, with the greatest difference between high dose atorvastatin and low dose simvastatin. The numbers of events in the analyses were small.

  15. High Dose Atorvastatin Associated with Increased Risk of Significant Hepatotoxicity in Comparison to Simvastatin in UK GPRD Cohort

    Science.gov (United States)

    Clarke, Alan T.; Johnson, Paul C. D.; Hall, Gillian C.; Ford, Ian; Mills, Peter R.

    2016-01-01

    Background & Aims Occasional risk of serious liver dysfunction and autoimmune hepatitis during atorvastatin therapy has been reported. We compared the risk of hepatotoxicity in atorvastatin relative to simvastatin treatment. Methods The UK GPRD identified patients with a first prescription for simvastatin [164,407] or atorvastatin [76,411] between 1997 and 2006, but with no prior record of liver disease, alcohol-related diagnosis, or liver dysfunction. Incident liver dysfunction in the following six months was identified by biochemical value and compared between statin groups by Cox regression model adjusting for age, sex, year treatment started, dose, alcohol consumption, smoking, body mass index and comorbid conditions. Results Moderate to severe hepatotoxicity [bilirubin >60μmol/L, AST or ALT >200U/L or alkaline phosphatase >1200U/L] developed in 71 patients on atorvastatin versus 101 on simvastatin. Adjusted hazard ratio [AHR] for all atorvastatin relative to simvastatin was 1.9 [95% confidence interval 1.4–2.6]. High dose was classified as 40–80mg daily and low dose 10–20mg daily. Hepatotoxicity occurred in 0.44% of 4075 patients on high dose atorvastatin [HDA], 0.07% of 72,336 on low dose atorvastatin [LDA], 0.09% of 44,675 on high dose simvastatin [HDS] and 0.05% of 119,732 on low dose simvastatin [LDS]. AHRs compared to LDS were 7.3 [4.2–12.7] for HDA, 1.4 [0.9–2.0] for LDA and 1.5 [1.0–2.2] for HDS. Conclusions The risk of hepatotoxicity was increased in the first six months of atorvastatin compared to simvastatin treatment, with the greatest difference between high dose atorvastatin and low dose simvastatin. The numbers of events in the analyses were small. PMID:26983033

  16. Risk assessment of hepatotoxicity among tuberculosis and human immunodeficiency virus/AIDS-coinfected patients under tuberculosis treatment.

    Science.gov (United States)

    Ngouleun, Williams; Biapa Nya, Prosper Cabral; Pieme, Anatole Constant; Telefo, Phelix Bruno

    2016-12-01

    Tuberculosis (TB) is a worldwide public health problem. It is a contagious and grave disease caused by Mycobacterium tuberculosis. Current drugs such as isoniazid, pyrazinamide, and rifampicin used for the treatment of tuberculosis are potentially hepatotoxic and can lead to drug hepatitis. In order to improve the follow-up of TB patients in Cameroon, we carried out a study which aimed to evaluate the hepatotoxicity risk factors associated with anti-TB drugs. The studies were performed on 75 participants who had visited the Loum District Hospital located in the littoral region of Cameroon for their routine consultation. Participants have been selected based on pre-established criteria of inclusion and exclusion. Prior to the informed consent signature, patients were given compelling information about the objective and the result output of the study. They were questioned about antioxidant food and alcohol consumption as well as some clinical signs of hepatotoxicity such as fever, nausea, vomiting, and tiredness. The collected blood was tested for the determination of biochemical markers (transaminases and C-reactive protein) using standard spectrophotometric methods. Biochemical analysis of samples showed a significant increase (pfactors, antioxidant food consumption significantly reduced the liver injury patient percentage for the above parameters, whereas an opposite situation was observed with alcohol consumption between TB-coinfection and TB patients. Regarding the C-reactive protein results, the percentage of positive tests was very high among coinfected patients (40%) compared with the control (15%). The interactions between parameters related to alcohol consumption and intake of antioxidant foods showed a slight decrease in activity compared with interactions without food. The results showed that human immunodeficiency virus status and alcohol consumption constitutes aggravating factors for the occurrence of hepatic toxicity. In addition, the consumption of

  17. Nonalcoholic steatohepatitic (NASH) mice are protected from higher hepatotoxicity of acetaminophen upon induction of PPARα with clofibrate

    International Nuclear Information System (INIS)

    Donthamsetty, Shashikiran; Bhave, Vishakha S.; Mitra, Mayurranjan S.; Latendresse, John R.; Mehendale, Harihara M.

    2008-01-01

    The objective was to investigate if the hepatotoxic sensitivity in nonalcoholic steatohepatitic mice to acetaminophen (APAP) is due to downregulation of nuclear receptor PPARα via lower cell division and tissue repair. Male Swiss Webster mice fed methionine and choline deficient diet for 31 days exhibited NASH. On the 32nd day, a marginally toxic dose of APAP (360 mg/kg, ip) yielded 70% mortality in steatohepatitic mice, while all non steatohepatitic mice receiving the same dose survived. 14 C-APAP covalent binding, CYP2E1 protein, and enzyme activity did not differ from the controls, obviating increased APAP bioactivation as the cause of amplified APAP hepatotoxicity. Liver injury progressed only in steatohepatitic livers between 6 and 24 h. Cell division and tissue repair assessed by 3 H-thymidine incorporation and PCNA were inhibited only in the steatohepatitic mice given APAP suggesting that higher sensitivity of NASH liver to APAP-induced hepatotoxicity was due to lower tissue repair. The hypothesis that impeded liver tissue repair in steatohepatitic mice was due to downregulation of PPARα was tested. PPARα was downregulated in NASH. To investigate whether downregulation of PPARα in NASH is the critical mechanism of compromised liver tissue repair, PPARα was induced in steatohepatitic mice with clofibrate (250 mg/kg for 3 days, ip) before injecting APAP. All clofibrate pretreated steatohepatitic mice receiving APAP exhibited lower liver injury, which did not progress and the mice survived. The protection was not due to lower bioactivation of APAP but due to higher liver tissue repair. These findings suggest that inadequate PPARα expression in steatohepatitic mice sensitizes them to APAP hepatotoxicity

  18. Hepatoprotective and Antioxidant activity of Scoparia dulcis Linn, against N Nitrosodiethylamine (DEN) induced Hepatotoxicity in experimental Rats

    OpenAIRE

    Langeswaran K; Jagadeesan A. J; Vijayaprakash S; Balasubramanian M. P

    2012-01-01

    Scoparia dulcis Linn, belongs to the family Scrophulariaceae and have speculated Medicinal properties. In this present investigation, the antioxidant and hepatoprotective activity of the aqueous extracts of Scoparia dulcis was evaluated against N-nitrosodiethylamine (DEN) induced liver cirrhosis in experimental rats. In group III hepatotoxicity induced animals, an oral dose of 500 mg/kg, of the aqueous extracts of Scoparia dulcis exhibited a significant (P

  19. Chemical Diversity Investigation of Hepatotoxic Pyrrolizidine Alkaloids in Qianliguang (Senecio scandens and Related Species by UHPLC-QTOF-MS

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    Lin Zhu

    2015-04-01

    Full Text Available Objective: Qianliguang (Senecio scandens is a common Chinese medicinal herb. Qianliguang-containing herbal proprietary products are registered as over-the-counter remedies in China and exported to Western countries. The presence of hepatotoxic pyrrolizidine alkaloids (PAs has raised concerns about the safety of using Qianliguang and its products. The present study aims at investigation of different types of PAs present in Qianliguang collected from representative locations in China.

  20. A retrospective review of methotrexate-induced hepatotoxicity among patients with psoriasis in a tertiary dermatology center in Malaysia.

    Science.gov (United States)

    Ng, Lim Chui; Lee, Yin Yin; Lee, Chew Kek; Wong, Su-Ming

    2013-01-01

    Methotrexate (MTX) is a common and efficacious systemic agent used for the treatment of moderate to severe psoriasis. Nevertheless, its use is associated with the risk of hepatotoxicity. This study was performed to study the association of MTX dose with regards to hepatotoxicity as evidenced by deranged transaminases. This was a retrospective review of patients with psoriasis on MTX from 2000 to 2009 at the outpatient dermatology clinic, University Malaya Medical Centre (UMMC). We analyzed patients' demography, serial laboratory investigations, liver ultrasounds, and liver biopsies of patients on MTX. Sixty-six of 710 (9.30%) patients with psoriasis were prescribed MTX throughout the 10-year period. Among them 57.6% developed deranged transaminases, with six requiring MTX withdrawal due to hepatotoxicity. The mean cumulative dose of MTX at the detection of liver enzyme derangement was 552.3 ± 596.1 mg. A high proportion of patients on MTX had deranged transaminases. However, the number of serious events was low. We concluded from this study that the use of MTX is relatively safe in patients with moderate to severe psoriasis. © 2013 The International Society of Dermatology.

  1. Suppression of Oncolytic Adenovirus-Mediated Hepatotoxicity by Liver-Specific Inhibition of NF-κB

    Directory of Open Access Journals (Sweden)

    Mitsuhiro Machitani

    2017-12-01

    Full Text Available Telomerase-specific replication-competent adenoviruses (Ads, i.e., TRADs, which possess an E1 gene expression cassette driven by the human telomerase reverse transcriptase promoter, are promising agents for cancer treatment. However, even though oncolytic Ads, including TRAD, are intratumorally administered, they are disseminated from the tumor to systemic circulation, causing concern about oncolytic Ad-mediated hepatotoxicity (due mainly to leaky expression of Ad genes in liver. We reported that inhibition of nuclear factor-κB (NF-κB leads to the suppression of replication-incompetent Ad vector-mediated hepatotoxicity via reduction of the leaky expression of Ad genes in liver. Here, to develop a TRAD with an improved safety profile, we designed a TRAD that carries a liver-specific promoter-driven dominant-negative IκBα (DNIκBα expression cassette (TRAD-DNIκBα. Compared with a conventional TRAD, TRAD-DNIκBα showed hepatocyte-specific inhibition of NF-κB signaling and significantly reduced Ad gene expression and replication in the normal human hepatocyte cell line. TRAD-induced hepatotoxicity was largely suppressed in mice following intravenous administration of TRAD-DNIκBα. However, the replication profiles and oncolytic activities of TRAD-DNIκBα were comparable with those of the conventional TRAD in human non-hepatic tumor cells. These results indicate that oncolytic Ads containing the liver-specific DNIκBα expression cassette have improved safety profiles without inhibiting oncolytic activities.

  2. Strain differences of cadmium-induced hepatotoxicity in Wistar-Imamichi and Fischer 344 rats: involvement of cadmium accumulation

    International Nuclear Information System (INIS)

    Shimada, Hideaki; Takamure, Yasutaka; Shimada, Akinori; Yasutake, Akira; Waalkes, Michael P.; Imamura, Yorishige

    2004-01-01

    We previously reported that Wistar-Imamichi (WI) rats have a strong resistance to cadmium (Cd)-induced lethality compared to other strains such as Fischer 344 (Fischer) rats. The present study was designed to establish biochemical and histological differences in Cd toxicity in WI and Fischer rats, and to clarify the mechanistic basis of these strain differences. A single Cd (4.5 mg/kg, s.c.) treatment caused a significant increase in serum alanine aminotransferase activity, indicative of hepatotoxicity, in Fischer rats, but did not in WI rats. This difference in hepatotoxic response to Cd was supported by pathological analysis. After treatment with Cd at doses of 3.0, 3.5 and 4.5 mg/kg, the hepatic and renal accumulation of Cd was significantly lower in the WI rats than in the Fischer rats, indicating a kinetic mechanism for the observed strain differences in Cd toxicity. Thus, the remarkable resistance to Cd-induced hepatotoxicity in WI rats is associated, at least in part, with a lower tissue accumulation of the metal. Hepatic and renal zinc (Zn) contents after administration were similarly lower in WI than in Fischer rats. When Zn was administered in combination with Cd to Fischer rats, it decreased Cd contents in the liver and kidney, and exhibited a significant protective effect against the toxicity of Cd. We propose the possibility that Zn transporter plays an important role in the strain difference of Cd toxicity in WI and Fischer rats

  3. In Vitro Model for Hepatotoxicity Studies Based on Primary Human Hepatocyte Cultivation in a Perfused 3D Bioreactor System.

    Science.gov (United States)

    Knöspel, Fanny; Jacobs, Frank; Freyer, Nora; Damm, Georg; De Bondt, An; van den Wyngaert, Ilse; Snoeys, Jan; Monshouwer, Mario; Richter, Marco; Strahl, Nadja; Seehofer, Daniel; Zeilinger, Katrin

    2016-04-16

    Accurate prediction of the potential hepatotoxic nature of new pharmaceuticals remains highly challenging. Therefore, novel in vitro models with improved external validity are needed to investigate hepatic metabolism and timely identify any toxicity of drugs in humans. In this study, we examined the effects of diclofenac, as a model substance with a known risk of hepatotoxicity in vivo, in a dynamic multi-compartment bioreactor using primary human liver cells. Biotransformation pathways of the drug and possible effects on metabolic activities, morphology and cell transcriptome were evaluated. Formation rates of diclofenac metabolites were relatively stable over the application period of seven days in bioreactors exposed to 300 µM diclofenac (300 µM bioreactors (300 µM BR)), while in bioreactors exposed to 1000 µM diclofenac (1000 µM BR) metabolite concentrations declined drastically. The biochemical data showed a significant decrease in lactate production and for the higher dose a significant increase in ammonia secretion, indicating a dose-dependent effect of diclofenac application. The microarray analyses performed revealed a stable hepatic phenotype of the cells over time and the observed transcriptional changes were in line with functional readouts of the system. In conclusion, the data highlight the suitability of the bioreactor technology for studying the hepatotoxicity of drugs in vitro.

  4. In Vitro Model for Hepatotoxicity Studies Based on Primary Human Hepatocyte Cultivation in a Perfused 3D Bioreactor System

    Directory of Open Access Journals (Sweden)

    Fanny Knöspel

    2016-04-01

    Full Text Available Accurate prediction of the potential hepatotoxic nature of new pharmaceuticals remains highly challenging. Therefore, novel in vitro models with improved external validity are needed to investigate hepatic metabolism and timely identify any toxicity of drugs in humans. In this study, we examined the effects of diclofenac, as a model substance with a known risk of hepatotoxicity in vivo, in a dynamic multi-compartment bioreactor using primary human liver cells. Biotransformation pathways of the drug and possible effects on metabolic activities, morphology and cell transcriptome were evaluated. Formation rates of diclofenac metabolites were relatively stable over the application period of seven days in bioreactors exposed to 300 µM diclofenac (300 µM bioreactors (300 µM BR, while in bioreactors exposed to 1000 µM diclofenac (1000 µM BR metabolite concentrations declined drastically. The biochemical data showed a significant decrease in lactate production and for the higher dose a significant increase in ammonia secretion, indicating a dose-dependent effect of diclofenac application. The microarray analyses performed revealed a stable hepatic phenotype of the cells over time and the observed transcriptional changes were in line with functional readouts of the system. In conclusion, the data highlight the suitability of the bioreactor technology for studying the hepatotoxicity of drugs in vitro.

  5. Acute ethanol administration reduces the antidote effect of N-acetylcysteine after acetaminophen overdose in mice

    DEFF Research Database (Denmark)

    Dalhoff, K; Hansen, P B; Ott, P

    1991-01-01

    given ethanol or saline alone only 7% and 3%, respectively, survived 96 h. 4. The data suggest that the protective effect of N-acetylcysteine on acetaminophen-induced toxicity in fed mice is reduced by concomitant administration of ethanol. This may explain the clinical observation that ingestion...

  6. Hepatoprotective Effect of Pandanus odoratissimus L Inflorescence ...

    African Journals Online (AJOL)

    Purpose: To investigate the hepatoprotective activity of methanol extracts of peduncles, flowers and spathes of Pandanus odoratissimus L. inflorescence in acetaminophen-induced hepatotoxicity in guinea pigs. Methods: The animals were randomly assigned to 9 groups (3 animals per group) and treated orally for 10 ...

  7. Toxicidad hepática por medicamentos antituberculosos Hepatotoxicity induced by antituberculosis drugs

    Directory of Open Access Journals (Sweden)

    Isabel Eugenia Escobar Toledo

    2008-01-01

    Full Text Available

    El fenómeno de la toxicidad hepática inducida por medicamentos cobró relevancia hace algunos años con el estudio de las reacciones adversas a medicamentos. El daño producido en el hígado por un xenobiótico que altera su función es lo que se conoce como toxicidad hepática. La importancia de reconocer y diagnosticar la toxicidad hepática por medicamentos estriba en su gravedad potencial; no en vano es la causa más frecuente por la que la industria farmacéutica retira medicamentos. La tuberculosis es una pandemia que afecta a gran parte de la población mundial y junto con el VIH es una enfermedad cada vez más frecuente en Colombia. Esta enfermedad se puede considerar como una situación especial porque para su tratamiento es preciso suministrar, por largos períodos, medicamentos con potencial tóxico para el hígado.

     

    El objetivo de este artículo es revisar algunos aspectos relacionados con la toxicidad hepática secundaria a medicamentos antituberculosos, tales como: epidemiología, factores de riesgo, mecanismos de toxicidad, manifestaciones clínicas, diagnóstico, tratamiento y seguimiento.

    Hepatotoxicity is the alteration of liver structure and function induced by either drugs or other substances. The importance of its proper diagnosis rests on its potential severity. It is the most frequent reason by which the pharmaceutical industry withdraws its products. Tuberculosis is a pandemic infection affecting a large proportion of the world population. Together with HIV infection it is becoming ever more frequent in Colombia. Tuberculosis poses

  8. The impact of partial manganese superoxide dismutase (SOD2)-deficiency on mitochondrial oxidant stress, DNA fragmentation and liver injury during acetaminophen hepatotoxicity

    International Nuclear Information System (INIS)

    Ramachandran, Anup; Lebofsky, Margitta; Weinman, Steven A.; Jaeschke, Hartmut

    2011-01-01

    Acetaminophen (APAP) hepatotoxicity is the most frequent cause of acute liver failure in many countries. The mechanism of cell death is initiated by formation of a reactive metabolite that binds to mitochondrial proteins and promotes mitochondrial dysfunction and oxidant stress. Manganese superoxide dismutase (SOD2) is a critical defense enzyme located in the mitochondrial matrix. The objective of this investigation was to evaluate the functional consequences of partial SOD2-deficiency (SOD2+/-) on intracellular signaling mechanisms of necrotic cell death after APAP overdose. Treatment of C57Bl/6J wild type animals with 200 mg/kg APAP resulted in liver injury as indicated by elevated plasma alanine aminotransferase activities (2870 ± 180 U/L) and centrilobular necrosis at 6 h. In addition, increased tissue glutathione disulfide (GSSG) levels and GSSG-to-GSH ratios, delayed mitochondrial GSH recovery, and increased mitochondrial protein carbonyls and nitrotyrosine protein adducts indicated mitochondrial oxidant stress. In addition, nuclear DNA fragmentation (TUNEL assay) correlated with translocation of Bax to the mitochondria and release of apoptosis-inducing factor (AIF). Furthermore, activation of c-jun-N-terminal kinase (JNK) was documented by the mitochondrial translocation of phospho-JNK. SOD2+/- mice showed 4-fold higher ALT activities and necrosis, an enhancement of all parameters of the mitochondrial oxidant stress, more AIF release and more extensive DNA fragmentation and more prolonged JNK activation. Conclusions: the impaired defense against mitochondrial superoxide formation in SOD2+/- mice prolongs JNK activation after APAP overdose and consequently further enhances the mitochondrial oxidant stress leading to exaggerated mitochondrial dysfunction, release of intermembrane proteins with nuclear DNA fragmentation and more necrosis.

  9. Studying preventive effects of Berberisintegerrimaon root on carbon tetrachloride induced hepatotoxicity in broilers

    Directory of Open Access Journals (Sweden)

    mohammadreza mohammadimalayeri

    2013-11-01

    Full Text Available Liver diseases and their economic losses have gained more importancealongside the development of integrated poultry industry. Studies have proved hepatotoxicity induced by carbon tetrachloride as one of the best experimental models of hepatotocicity. Barberries have been used widely in traditional medicine.The purpose of the present study was to evaluaterthe preventive effects of Berberisintegerrima root on carbon tetrachloride induced liver lesions in broilers.For this purpose, 80 day old Ross strain broilers were divided randomly to 8 study groupsconsisting of negative control, positive control which received IP 4ml/kg b.w. carbon tetrachloride twice in 25th and 28thdays , treatment controls consisting of 10,20 and 30 grams of  Berberisintegerrima root per kilogram of diet and treatment groups consisting of 10,20 and 30 gr. Of Berberis root / Kg diet + IPcarbontetrachloride 4ml/Kg b.w. twice in 25th and 28th days.At 29th day, blood samples were collected from animals, then they were sacrificed and their liver samples were fixed in 10% formalin solution. The blood samples were sent to laboratory to measure ALT,AST and ALP activities.Biochemical results didn't show any significant changes of ALT,AST and ALP activities between all study groups (P>0.05. Microscopic results showed significant decrease in pathologic lesions of 20 gr Berberis root /Kg diet treatment group in comparison with the positive control group(P

  10. A three-stage-integrative approach for the identification of potential hepatotoxic compounds from botanical products.

    Science.gov (United States)

    Jin, Yecheng; Zhao, Xiaoping; Zhang, Yufeng; Li, Xiang; Nie, Xiaojing; Wang, Yi; Fan, Xiaohui

    2011-05-01

    With the increasing use of herbal medicines and dietary supplements, intensive concerns about their potential toxicities have been raised. Screening and identifying the toxic compounds from these botanical products composed by hundreds of components have become a critical but challenging problem. In this study, 3 methods, including fraction separation, an in-house-developed fluorescein diacetate-based automatic microscopy screening (FAMS) platform, and liquid chromatography-mass spectrometry-based compounds identification were integrated within the Three-Stage-Integrative (TSI) approach for the identification of potential hepatotoxicants from botanical products. The sensitivity and linear range of FAMS assay was validated and compared with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay by previously reported hepatotoxic compounds. The success of TSI approach was further demonstrated by its application to Fructus aristolochiae. Aristolochic acid IVa and aristolodione were tentatively identified to be potential hepatotoxicants in this plant. These applications suggested that our TSI approach provides an effective tool for identifying potential toxic compounds from botanical products.

  11. Dideoxynucleoside HIV reverse transcriptase inhibitors and drug-related hepatotoxicity: a case report

    Directory of Open Access Journals (Sweden)

    Lapadula Giuseppe

    2007-05-01

    Full Text Available Abstract This report regards the case of a 43 year-old HIV-positive woman who developed an episode of serious transaminase elevation during stavudine-including antiretroviral therapy. Diagnostic assessment ruled out hepatitis virus co-infection, alcohol abuse besides other possible causes of liver damage. No signs of lactic acidosis were present. Liver biopsy showed portal inflammatory infiltrate, spotty necrosis, vacuoles of macro- and micro-vesicular steatosis, acidophil and foamy hepatocytes degeneration with organelles clumping, poorly formed Mallory bodies and neutrophil granulocytes attraction (satellitosis. A dramatic improvement in liver function tests occurred when stavudine was discontinued and a new antiretroviral regimen with different nucleoside reverse transcriptase inhibitors was used. The importance of considering hepatotoxicity as an adverse event of HAART including stavudine, even in absence of other signs of mitochondrial toxicity should therefore be underlined. Liver biopsy may provide further important information regarding patients with severe transaminase elevation, for a better understanding of the etiology of liver damage.

  12. Hepatotoxic Seafood Poisoning (HSP Due to Microcystins: A Threat from the Ocean?

    Directory of Open Access Journals (Sweden)

    Evangelos Briasoulis

    2013-08-01

    Full Text Available Cyanobacterial blooms are a major and growing problem for freshwater ecosystems worldwide that increasingly concerns public health, with an average of 60% of blooms known to be toxic. The most studied cyanobacterial toxins belong to a family of cyclic heptapeptide hepatotoxins, called microcystins. The microcystins are stable hydrophilic cyclic heptapeptides with a potential to cause cell damage following cellular uptake via organic anion-transporting proteins (OATP. Their intracellular biologic effects presumably involve inhibition of catalytic subunits of protein phosphatases (PP1 and PP2A and glutathione depletion. The microcystins produced by cyanobacteria pose a serious problem to human health, if they contaminate drinking water or food. These toxins are collectively responsible for human fatalities, as well as continued and widespread poisoning of wild and domestic animals. Although intoxications of aquatic organisms by microcystins have been widely documented for freshwater ecosystems, such poisonings in marine environments have only occasionally been reported. Moreover, these poisonings have been attributed to freshwater cyanobacterial species invading seas of lower salinity (e.g., the Baltic or to the discharge of freshwater microcystins into the ocean. However, recent data suggest that microcystins are also being produced in the oceans by a number of cosmopolitan marine species, so that Hepatotoxic Seafood Poisoning (HSP is increasingly recognized as a major health risk that follows consumption of contaminated seafood.

  13. Evaluation of Antitrypanosomal Dihydroquinolines for Hepatotoxicity, Mutagenicity, and Methemoglobin Formation In Vitro.

    Science.gov (United States)

    Werbovetz, Karl A; Riccio, Edward S; Furimsky, Anna; Richard, Julian V; He, Shanshan; Iyer, Lalitha; Mirsalis, Jon

    2014-07-01

    N1-Benzylated dihydroquinolin-6-ols and their corresponding esters display exceptional activity against African trypanosomes in vitro, and administration of members of this class of compounds to trypanosome-infected mice results in cures in a first-stage African trypanosomiasis model. Since a quinone imine intermediate has been implicated in the antiparasitic mechanism of action of these compounds, evaluation of the hepatotoxic, mutagenic, and methemoglobin-promoting effects of these agents was performed. 1-Benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride and 1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate showed outstanding in vitro selectivity for Trypanosoma brucei compared to the HepG2, Hep3B, Huh7, and PLC5 hepatocyte cell lines. 1-Benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride and 1-(2-methoxybenzyl)-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate were not mutagenic when screened in the Ames assay, with or without metabolic activation. The latter 2 compounds promoted time- and dose-dependent formation of methemoglobin when incubated in whole human blood, but such levels were below those typically required to produce symptoms of methemoglobinemia in humans. Although compounds capable of quinone imine formation require careful evaluation, these in vitro studies indicate that antitrypanosomal dihydroquinolines merit further study as drug candidates against the neglected tropical disease human African trypanosomiasis. © The Author(s) 2014.

  14. Antioxidant activity of Green tea extract against Isoniazid induced hepatotoxicity in the rats

    Directory of Open Access Journals (Sweden)

    2011-08-01

    Full Text Available Tuberculosis continues to be a common health problem worldwide. Isoniazid, an antibiotic used routinely for tuberculosis chemotherapy is documented to be a potent hepatotoxicant. The aim of the present study was to assess the antioxidant activity of Green tea extract (GTE against Isoniazid induced hepatotoxicity in the rats. Male Wistar rats were randomly assigned into 4 groups of 10 animals each including 1- normal healthy control rats, 2- healthy rats receiving (GTE 3- toxicant control, and 4- toxicant drug+ GTE treatment group. In groups 2 and 4 GTE (1.5%, w/v was given as only source of drinking for 8 weeks. In the midst stage of experiment (4th and 5th weeks, Isonizid (50 mg/kg b.w./day, i.p. was administrated for groups 3 and 4 for a period of 2 weeks. At the end of experiment, product of lipid peroxidation (MDA, activities of superoxide dismutase (SOD, catalase (CAT, glutathione peroxidase (GPX and glutathione reductase (GR were assayed in liver homogenates to evaluate antioxidant activity. Significant differences among the groups were determined by one-way analysis of variance followed by Tukey post-test. Statistical significance was considered at p

  15. Ursodeoxycholic Acid Can Improve Liver Transaminase Quantities in Children with Anticonvulsant Drugs Hepatotoxicity: a Pilot Study.

    Directory of Open Access Journals (Sweden)

    Masoumeh Asgarshirazi

    2015-06-01

    Full Text Available The present study has been directed to investigate Ursodeoxycholic Acid (UDCA effect in children, to reduce the high Liver transaminases induced by Anticonvulsant drugs (drug induced hepatitis. This idea has been driven from Cytoprotective and antioxidant properties of UDCA to be used in drug induced inflammation in Liver. Twenty two epileptic patients aged between 4 mo - 3 yr whom were under anticonvulsant therapy with drugs such as valperoic acid, primidone, levetiracetam, Phenobarbital or any combination of them and had shown Liver transaminases rise , after rule out of Viral-Autoimmune, Metabolic and Anatomic causes, have been prescribed UDCA in dose of 10-15 mg/kg/day, at least for 6 months. Any patient who have shown confusing factors such as genetic disorders with liver involvement or spontaneous decline in enzymes or had not treatment compliance has been excluded from the study. Transaminases range changes as well as Probable side effects of the drug have been monitored. The results indicated that UDCA is effective and well tolerable in the children with drug induced hyper transaminasemia. No side effect has been seen and recorded in this study. Based on this study and its results, we recommend UDCA as a safe and effective choice in drug induced hepatotoxicities.

  16. Immunization of Mice with Anthrax Protective Antigen Limits Cardiotoxicity but Not Hepatotoxicity Following Lethal Toxin Challenge

    Directory of Open Access Journals (Sweden)

    T. Scott Devera

    2015-06-01

    Full Text Available Protective immunity against anthrax is inferred from measurement of vaccine antigen-specific neutralizing antibody titers in serum samples. In animal models, in vivo challenges with toxin and/or spores can also be performed. However, neither of these approaches considers toxin-induced damage to specific organ systems. It is therefore important to determine to what extent anthrax vaccines and existing or candidate adjuvants can provide organ-specific protection against intoxication. We therefore compared the ability of Alum, CpG DNA and the CD1d ligand α-galactosylceramide (αGC to enhance protective antigen-specific antibody titers, to protect mice against challenge with lethal toxin, and to block cardiotoxicity and hepatotoxicity. By measurement of serum cardiac Troponin I (cTnI, and hepatic alanine aminotransferase (ALT, and aspartate aminotransferase (AST, it was apparent that neither vaccine modality prevented hepatic intoxication, despite high Ab titers and ultimate survival of the subject. In contrast, cardiotoxicity was greatly diminished by prior immunization. This shows that a vaccine that confers survival following toxin exposure may still have an associated morbidity. We propose that organ-specific intoxication should be monitored routinely during research into new vaccine modalities.

  17. Protective role of tetrahydrocurcumin (THC) an active principle of turmeric on chloroquine induced hepatotoxicity in rats.

    Science.gov (United States)

    Pari, Leelavinothan; Amali, D Rosalin

    2005-04-30

    Tetrahydrocurcumin (THC) is an antioxidative substance, which is derived from curcumin, the component of turmeric. In the present investigation, the effect of THC and curcumin against chloroquine (CQ) induced hepatotoxicity were studied in female Wistar rats. On single oral administration of CQ (970 mg/kg body weight) the activities of serum marker enzymes namely aspartate transaminase, alanine transaminase and alkaline phosphatase and the levels of bilirubin were significantly increased with significant alterations of lipids in serum and lipidperoxidation markers such as thiobarbituric acid reactive substances (TBARS) and hydroperoxides in plasma and liver were also elevated in CQ treated rats. The levels of non-enzymic antioxidants (vitamin C, vitamin E and reduced glutathione) and enzymic antioxidants (superoxide dismutase, catalase and glutathione peroxidase) were also decreased in CQ treated rats. Administration of THC (80 mg/kg body weight) and curcumin (80 mg/kg body weight) for 8 days before and 7 days after single administration of CQ significantly decreased the activities of serum markers and lipids in serum. In addition, the level of TBARS and hydroperoxides were significantly decreased with significant increase in non-enzymic and enzymic antioxidants on treatment with THC and curcumin. The biochemical observation was supplemented by histopathological examination of liver section. The results of the study reveal that THC shows more pronounced protective effect than curcumin against CQ induced toxicity.

  18. Determinants of hepatotoxicity after repeated supratherapeutic paracetamol ingestion: systematic review of reported cases.

    Science.gov (United States)

    Acheampong, Paul; Thomas, Simon H L

    2016-10-01

    To evaluate the role of reported daily dose, age and other risk factors, and to assess the value of quantifying serum transaminase activity and paracetamol (acetaminophen) concentration at initial assessment for identifying patients at risk of hepatotoxicity following repeated supratherapeutic paracetamol ingestion (RSPI). Systematic literature review with collation and analysis of individual-level data from reported cases of RSPI associated with liver damage. In 199 cases meeting the selection criteria, severe liver damage (ALT/AST ≥1000 IU l(-1) , liver failure or death) was reported in 186 (93%) cases including 77/78 (99%) children aged ≤6 years. Liver failure occurred in 127 (64%) cases; of these 49 (39%) died. Maximum ingested daily paracetamol doses were above UK recommendations in 143 (72%) patients. US-Australasian thresholds for repeated supratherapeutic ingestions requiring intervention were not met in 71 (36%) cases; of these 35 (49%) developed liver failure and 10 (14%) died. No cases developing liver damage had paracetamol concentration Paracetamol concentrations <20 mg l(-1) with normal serum ALT/AST activity on initial assessment suggests a low risk of subsequent liver damage. These findings are, however, limited by low patient numbers, publication bias and the accuracy of the histories in reported cases. © 2016 The British Pharmacological Society.

  19. Genetic polymorphisms of N-acetyltransferase 2 & susceptibility to antituberculosis drug-induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Surendra K Sharma

    2016-01-01

    Full Text Available Background & objectives: The N-acetyltransferase 2 (NAT2 gene encodes an enzyme which both activates and deactivates arylamine and other drugs and carcinogens. This study was aimed to investigate the role of NAT2 gene polymorphism in anti-tuberculosis drug-induced hepatotoxicity (DIH. Methods: In this prospective study, polymerase chain reaction-restriction fragment length polymorphism results for NAT2 gene were compared between 185 tuberculosis patients who did not develop DIH and 105 tuberculosis patients who developed DIH while on anti-tuberculosis drugs. Results: Frequency of slow-acetylator genotype was commonly encountered and was not significantly different between DIH (82.8% and non-DIH (77.2% patients. However, the genotypic distribution of variant NAT2FNx015/FNx017 amongst slow-acetylator genotypes was significantly higher in DIH (56% group as compared to non-DIH (39% group (odds ratio 2.02; P=0.006. Interpretation & conclusions: The present study demonstrated no association between NAT2 genotype and DIH in the north Indian patients with tuberculosis.

  20. Amelioration of lead induced hepatotoxicity by Allium sativum extracts in Swiss albino mice

    Directory of Open Access Journals (Sweden)

    Sharma A

    2010-01-01

    Full Text Available Lead is a blue-gray and highly toxic divalent metal that occurs naturally in the earth crust and isspread throughout the environment by various human activities. The efficacy of garlic (Allium sativumto reduce hepatotoxicity induced by lead nitrate was evaluated experimentally in male mice. Oraltreatment with lead nitrate at a dose of 50 mg/ kg body weight daily for 40 days (1/45 of LD50 induceda significant increase in the levels of hepatic aspartate aminotransferase (AST, alanineaminotransferase (ALT, alkaline phosphatase (ALP, acid phosphatase (ALP, cholesterol, lipidperoxidation (LPO and lead nitrate. In parallel, hepatic protein levels in lead exposed mice weresignificantly depleted. Lead nitrate exposure also produced detrimental effects on the redox status ofthe liver indicated by a significant decline in the levels of liver antioxidants such as superoxidedismutase (SOD, catalase (CAT and glutathione (GSH. After exposure to lead nitrate (50 mg/kgbody weight for 10 days, the animals received aqueous garlic extract (250 mg/ kg body weight and500 mg/ kg body weight and ethanolic garlic extract (100 mg/ kg body weight and 250 mg/ kg bodyweight and partially restored the deranged parameters significantly Histological examination of theliver also revealed pathophysiological changes in lead nitrate exposed group and treatment with garlicimproved liver histology. Our data suggest that garlic is a phytoantioxidant that can counteract thedeleterious effects of lead nitrate.

  1. EJST V9N2

    African Journals Online (AJOL)

    Acute oral toxicity study of Thymus serrulatus and Thymus schimperi from Ethiopia. Destaw Damtie1* ..... weight ratio, liver to body weight ratio and brain to body weight ratio in the .... oil in experimental model of acetaminophen- induced injury.

  2. Mouse strain-dependent caspase activation during acetaminophen hepatotoxicity does not result in apoptosis or modulation of inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Williams, C. David [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Koerner, Michael R., E-mail: mkoern2@illinois.edu [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Lampe, Jed N. [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Farhood, Anwar [Department of Pathology, Brackenridge Hospital, Austin, TX 78701 (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States)

    2011-12-15

    activity. Black-Right-Pointing-Pointer Caspase-3 activity does not result in increased hepatocellular apoptotic cell death. Black-Right-Pointing-Pointer Neutrophil recruitment during acetaminophen occurs independently of nutritional status. Black-Right-Pointing-Pointer Fed or fasted state does not alter the mechanisms of acetaminophen-induced cell death.

  3. Unusual Synchronous Methimazole-Induced Agranulocytosis and Severe Hepatotoxicity in Patient with Hyperthyroidism: A Case Report and Review of the Literature

    Science.gov (United States)

    Yang, Jun; Zhang, Jun; Xu, Qin; Sheng, Guo-ping; Weng, Wan-wen; Dong, Meng-jie

    2015-01-01

    Context. To report a patient with hyperthyroidism who developed concurrent occurrence of agranulocytosis and severe hepatotoxicity after taking methimazole (MMI). Case. A 51-year-old Chinese male was diagnosed as hyperthyroidism with normal white blood count and liver function. After 4 weeks' treatment with MMI 20 mg/d, it developed to agranulocytosis and severe cholestatic hepatotoxicity. The patient's symptoms and laboratory abnormalities disappeared after the withdrawal of MMI; his white blood count and liver function recover to normal in 2 weeks and 5 weeks, respectively. 296 MBq dose of 131I was given to the patient 3 weeks after the withdrawal of MMI and his thyroid function was back to normal in 6 months. As we know through literature review, only 5 previous cases reported the synchronous ATD-induced agranulocytosis and severe hepatotoxicity in patients with hyperthyroidism. Methods. Review of the patient's clinical course. Literature review of cases of hyperthyroidism with agranulocytosis and severe hepatotoxicity demonstrated that these complications occurred after taking antithyroid drug (ATD). Conclusions. Patient with hyperthyroidism can have synchronous ATD-induced agranulocytosis and severe hepatotoxicity. This case is extremely rare, but the adverse effects with ATDs is clinically significant. The clinicians need to be careful about this and monitor biochemical of patients who take ATDs. PMID:26060496

  4. Unusual Synchronous Methimazole-Induced Agranulocytosis and Severe Hepatotoxicity in Patient with Hyperthyroidism: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Jun Yang

    2015-01-01

    Full Text Available Context. To report a patient with hyperthyroidism who developed concurrent occurrence of agranulocytosis and severe hepatotoxicity after taking methimazole (MMI. Case. A 51-year-old Chinese male was diagnosed as hyperthyroidism with normal white blood count and liver function. After 4 weeks’ treatment with MMI 20 mg/d, it developed to agranulocytosis and severe cholestatic hepatotoxicity. The patient’s symptoms and laboratory abnormalities disappeared after the withdrawal of MMI; his white blood count and liver function recover to normal in 2 weeks and 5 weeks, respectively. 296 MBq dose of 131I was given to the patient 3 weeks after the withdrawal of MMI and his thyroid function was back to normal in 6 months. As we know through literature review, only 5 previous cases reported the synchronous ATD-induced agranulocytosis and severe hepatotoxicity in patients with hyperthyroidism. Methods. Review of the patient’s clinical course. Literature review of cases of hyperthyroidism with agranulocytosis and severe hepatotoxicity demonstrated that these complications occurred after taking antithyroid drug (ATD. Conclusions. Patient with hyperthyroidism can have synchronous ATD-induced agranulocytosis and severe hepatotoxicity. This case is extremely rare, but the adverse effects with ATDs is clinically significant. The clinicians need to be careful about this and monitor biochemical of patients who take ATDs.

  5. Acute-on-chronic liver failure due to thiamazole in a patient with hyperthyroidism and trilogy of Fallot: case report

    Directory of Open Access Journals (Sweden)

    Shen Chuan

    2010-08-01

    Full Text Available Abstract Background Thiamazole is a widely used antithyroid agent that has been approved for the treatment of hyperthyroidism. Although thiamazole-induced hepatotoxicity is a main side effect, it may progress to liver failure in a very few cases. Case Presentation We described a 24-year-old patient with hyperthyroidism and trilogy of Fallot, who developed liver failure due to thiamazole. Liver biopsy showed intrahepatic cholestasis, mild inflammatory infiltrates, as well as significant fibrosis, indicating both acute and chronic liver injuries. Although a series of potent therapies were given, the patient deceased due to severe liver decompensation. Conclusions This case suggests that thiamazole-induced hepatotoxicity in the setting of advanced fibrosis increases the risk of poor outcome. Regular liver function monitoring during thiamazole therapy is therefore important.

  6. Acute-on-chronic liver failure due to thiamazole in a patient with hyperthyroidism and trilogy of Fallot: case report

    Science.gov (United States)

    2010-01-01

    Background Thiamazole is a widely used antithyroid agent that has been approved for the treatment of hyperthyroidism. Although thiamazole-induced hepatotoxicity is a main side effect, it may progress to liver failure in a very few cases. Case Presentation We described a 24-year-old patient with hyperthyroidism and trilogy of Fallot, who developed liver failure due to thiamazole. Liver biopsy showed intrahepatic cholestasis, mild inflammatory infiltrates, as well as significant fibrosis, indicating both acute and chronic liver injuries. Although a series of potent therapies were given, the patient deceased due to severe liver decompensation. Conclusions This case suggests that thiamazole-induced hepatotoxicity in the setting of advanced fibrosis increases the risk of poor outcome. Regular liver function monitoring during thiamazole therapy is therefore important. PMID:20707932

  7. Acute hyperammonemic encephalopathy with features on diffusion-weighted images: Report of two cases

    International Nuclear Information System (INIS)

    Kim, Ja Young; Yu, In Kyu

    2015-01-01

    Acute hyperammonemic encephalopathy is a rare toxic encephalopathy caused by accumulated plasma ammonia. A few literatures are reported about MRI findings of acute hyperammonemic encephalopathy. It is different from the well-known chronic hepatic encephalopathy. The clinical symptom and MRI findings of acute hyperammonemic encephalopathy can be reversible with proper treatment. Acute hepatic encephalopathy involves the cingulate cortex, diffuse cerebral cortices, insula, bilateral thalami on diffusion-weighted imaging (DWI), and fluid-attenuated inversion-recovery. Acute hepatic encephalopathy might mimic hypoxic-ischemic encephalopathy because of their similar predominant involving sites. We experienced 2 cases of acute hyperammonemic encephalopathy consecutively. They showed restricted diffusion at the cingulate cortex, cerebral cortices, insula, and bilateral dorsomedial thalami on DWI. One patient underwent acute fulminant hepatitis A, the other patient with underlying chronic liver disease had acute liver failure due to hepatotoxicity of tuberculosis medication. In this report, we presented the characteristic features of DWI in acute hyperammonemic encephalopathy. In addition, we reviewed articles on MRI findings of acute hyperammonemic encephalopathy.

  8. Acute hyperammonemic encephalopathy with features on diffusion-weighted images: Report of two cases

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ja Young; Yu, In Kyu [Dept. of Radiology, Eulji University Hospital, Daejeon (Korea, Republic of)

    2015-02-15

    Acute hyperammonemic encephalopathy is a rare toxic encephalopathy caused by accumulated plasma ammonia. A few literatures are reported about MRI findings of acute hyperammonemic encephalopathy. It is different from the well-known chronic hepatic encephalopathy. The clinical symptom and MRI findings of acute hyperammonemic encephalopathy can be reversible with proper treatment. Acute hepatic encephalopathy involves the cingulate cortex, diffuse cerebral cortices, insula, bilateral thalami on diffusion-weighted imaging (DWI), and fluid-attenuated inversion-recovery. Acute hepatic encephalopathy might mimic hypoxic-ischemic encephalopathy because of their similar predominant involving sites. We experienced 2 cases of acute hyperammonemic encephalopathy consecutively. They showed restricted diffusion at the cingulate cortex, cerebral cortices, insula, and bilateral dorsomedial thalami on DWI. One patient underwent acute fulminant hepatitis A, the other patient with underlying chronic liver disease had acute liver failure due to hepatotoxicity of tuberculosis medication. In this report, we presented the characteristic features of DWI in acute hyperammonemic encephalopathy. In addition, we reviewed articles on MRI findings of acute hyperammonemic encephalopathy.

  9. GARLIC AMELIORATES THE HEPATOTOXIC EFFECT INDUCED BY THIOACETAMIDE IN FEMALE RATS

    International Nuclear Information System (INIS)

    OSMAN, H.F.; TAHA, M.S.

    2008-01-01

    The purpose of this study was to investigate the pretreatment effect of garlic on hepatotoxicity and oxidative stress induced by thioacetamide (TAA) in female albino rats.Sixty female adult albino rats were assigned equally into four groups; control group: animals without treatment, group ?: rats given daily oral dose of 250 mg/ kg garlic for 28 days, group ??: rats injected intraperitonealy by thioacetamide 20 mg ? kg for two weeks and group III: rats given 250 mg / kg garlic orally for 28 day followed by intrapertoneal injection of 20 mg / kg thioacetamide for two weeks. Liver enzymes were evaluated by measurements of AST, ALT and alkaline phosphatase and also trace elements (Cu and Zn) were estimated. Superoxide dismutase, glutathione peroxidase, malondialdehyde and thyroid hormones (T3 and T4) were assessed. Also, histological studies on liver and stomach were carried out. The results indicated that treatment with garlic significantly decreased liver enzymes (AST, ALT and ALP). Cu showed high significant increase in groups treated with garlic and also garlic + TAA, while Zn was increased significantly in TAA group. Superoxide dismutase (SOD) was increased significantly in group I while TAA decreased it significantly. Glutathione peroxidase was decreased significantly in group II while its level in group IV reached near the control value. Similarly, malondialdehyde was decreased significantly in garlic group and garlic ameliorated the thioacetamide effect in garlic + TAA group. The treatment with TAA led to significant increase in T3 and significant decrease in T4 hormones. Garlic ameliorated T3 level to reach the control level. Histologically, pre-treatment with garlic induced a prophylactic activity against the thioacetamide in liver and stomach tissues.According to the obtained results, it could be conclude that garlic treatment may act as antioxidant or pro-oxidant in TAA treated animals besides decreasing the TAA toxic effects on liver enzymes, liver and

  10. Metabolic activation of hepatotoxic drug (benzbromarone) induced mitochondrial membrane permeability transition

    Energy Technology Data Exchange (ETDEWEB)

    Shirakawa, Maho; Sekine, Shuichi; Tanaka, Ayaka [The Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba (Japan); Horie, Toshiharu [Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo (Japan); Ito, Kousei, E-mail: itokousei@chiba-u.jp [The Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba (Japan)

    2015-10-01

    The risk of drug-induced liver injury (DILI) is of great concern to the pharmaceutical industry. It is well-known that metabolic activation of drugs to form toxic metabolites (TMs) is strongly associated with DILI onset. Drug-induced mitochondrial dysfunction is also strongly associated with increased risk of DILI. However, it is difficult to determine the target of TMs associated with exacerbation of DILI because of difficulties in identifying and purifying TMs. In this study, we propose a sequential in vitro assay system to assess TM formation and their ability to induce mitochondrial permeability transition (MPT) in a one-pot process. In this assay system, freshly-isolated rat liver mitochondria were incubated with reaction solutions of 44 test drugs preincubated with liver microsomes in the presence or absence of NADPH; then, NADPH-dependent MPT pore opening was assessed as mitochondrial swelling. In this assay system, several hepatotoxic drugs, including benzbromarone (BBR), significantly induced MPT in a NADPH-dependent manner. We investigated the rationality of using BBR as a model drug, since it showed the most prominent MPT in our assay system. Both the production of a candidate toxic metabolite of BBR (1′,6-(OH){sub 2} BBR) and NADPH-dependent MPT were inhibited by several cytochrome P450 (CYP) inhibitors (clotrimazole and SKF-525A, 100 μM). In summary, this assay system can be used to evaluate comprehensive metabolite-dependent MPT without identification or purification of metabolites. - Highlights: • We constructed a sequential assay system for toxic metabolite induced MPT in one pot. • 14 drugs (e.g. benzbromarone (BBR)) induced toxic metabolite dependent MPT. • Both the production of toxic metabolite and MPT could be inhibited by CYP inhibitors. • This system could evaluate the comprehensive MPT without purification of metabolites.

  11. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

    International Nuclear Information System (INIS)

    Lake, April D.; Novak, Petr; Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D.; Lu, Zhenqiang; Lehman-McKeeman, Lois D.; Cherrington, Nathan J.

    2013-01-01

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ► Altered hepatic bile acid composition is observed in progressive NAFLD. ► Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ► Increased levels of taurine and conjugated bile acids

  12. Assessment of mitochondrial dysfunction-related, drug-induced hepatotoxicity in primary rat hepatocytes

    International Nuclear Information System (INIS)

    Liu, Cong; Sekine, Shuichi; Ito, Kousei

    2016-01-01

    Evidence that mitochondrial dysfunction plays a central role in drug-induced liver injury is rapidly accumulating. In contrast to physiological conditions, in which almost all adenosine triphosphate (ATP) in hepatocytes is generated in mitochondria via aerobic respiration, the high glucose content and limited oxygen supply of conventional culture systems force primary hepatocytes to generate most ATP via cytosolic glycolysis. Thus, such anaerobically poised cells are resistant to xenobiotics that impair mitochondrial function, and are not suitable to identify drugs with mitochondrial liabilities. In this study, primary rat hepatocytes were cultured in galactose-based medium, instead of the conventional glucose-based medium, and in hyperoxia to improve the reliance of energy generation on aerobic respiration. Activation of mitochondria was verified by diminished cellular lactate release and increased oxygen consumption. These conditions improved sensitivity to the mitochondrial complex I inhibitor rotenone. Since oxidative stress is also a general cause of mitochondrial impairment, cells were exposed to test compounds in the presence of transferrin to increase the generation of reactive oxygen species via increased uptake of iron. Finally, 14 compounds with reported mitochondrial liabilities were tested to validate this new drug-induced mitochondrial toxicity assay. Overall, the culture of primary rat hepatocytes in galactose, hyperoxia and transferrin is a useful model for the identification of mitochondrial dysfunction-related drug-induced hepatotoxicity. - Highlights: • Drug-induced mitochondrial toxicity was evaluated using primary rat hepatocytes. • Galactose and hyperoxia could activate OXPHOS in primary rat hepatocytes. • Cells with enhanced OXPHOS exhibit improved sensitivity to mitochondrial toxins. • Transferrin potentiate mitochondrial toxicity via increased ROS production.

  13. Effectiveness of hepatoprotective drugs for anti-tuberculosis drug-induced hepatotoxicity: a retrospective analysis

    Directory of Open Access Journals (Sweden)

    Zenya Saito

    2016-11-01

    Full Text Available Abstract Background The effectiveness of hepatoprotective drugs for DIH (drug induced hepatotoxicity during tuberculosis treatment is not clear. We evaluated the effectiveness of hepatoprotective drugs by comparing the period until the normalization of hepatic enzymes between patients who were prescribed with the hepatoprotective drugs after DIH was occurred and patients who were not prescribed with the hepatoprotective drugs. Methods During 2006–2010, 389 patients with active tuberculosis were included in this study. DIH was defined as elevation of peak serum aspartate aminotransferase (AST and/or alanine aminotransferase (ALT of more than twice the upper limit of normal (ULN. We divided the patients into the severe (peak serum AST and/or ALT elevation of >5 times the ULN, moderate (peak serum AST and/or ALT elevation of >3 to ≤5 times the ULN, and mild DIH groups (peak serum AST and/or ALT elevation of >2 to ≤3 times the ULN. We compared the average period until the normalization of hepatic enzymes between patient subgroups with and without hepatoprotective drugs (ursodeoxycholic acid: UDCA, stronger neo-minophagen C: SNMC, and glycyrrhizin. Results In the severe group, there was no significant difference in the average period until the normalization between subgroups with and without hepatoprotective drugs (21.4 ± 10.8 vs 21.5 ± 11.1 days, P = 0.97. In the mild group, the period was longer in the subgroup with hepatoprotective drugs than that without hepatoprotective drugs (15.7 ± 6.2 vs 12.4 ± 7.9 days, P = 0.046. Conclusion Regardless of the severity, hepatoprotective drugs did not shorten the period until the normalization of hepatic enzymes.

  14. Energy metabolism and biotransformation as endpoints to pre-screen hepatotoxicity using a liver spheroid model

    International Nuclear Information System (INIS)

    Xu Jinsheng; Purcell, Wendy M.

    2006-01-01

    The current study investigated liver spheroid culture as an in vitro model to evaluate the endpoints relevant to the status of energy metabolism and biotransformation after exposure to test toxicants. Mature rat liver spheroids were exposed to diclofenac, galactosamine, isoniazid, paracetamol, m-dinitrobenzene (m-DNB) and 3-nitroaniline (3-NA) for 24 h. Pyruvate uptake, galactose biotransformation, lactate release and glucose secretion were evaluated after exposure. The results showed that pyruvate uptake and lactate release by mature liver spheroids in culture were maintained at a relatively stable level. These endpoints, together with glucose secretion and galactose biotransformation, were related to and could reflect the status of energy metabolism and biotransformation in hepatocytes. After exposure, all of the test agents significantly reduced glucose secretion, which was shown to be the most sensitive endpoint of those evaluated. Diclofenac, isoniazid, paracetamol and galactosamine reduced lactate release (P < 0.01), but m-DNB increased lactate release (P < 0.01). Diclofenac, isoniazid and paracetamol also reduced pyruvate uptake (P < 0.01), while galactosamine had little discernible effect. Diclofenac, galactosamine, paracetamol and m-DNB also reduced galactose biotransformation (P < 0.01), by contrast, isoniazid did not. The metabolite of m-DNB, 3-NA, which served as a negative control, did not cause significant changes in lactate release, pyruvate uptake or galactose biotransformation. It is concluded that pyruvate uptake, galactose biotransformation, lactate release and glucose secretion can be used as endpoints for evaluating the status of energy metabolism and biotransformation after exposure to test agents using the liver spheroid model to pre-screen hepatotoxicity

  15. Mechanism-based biomarker gene sets for glutathione depletion-related hepatotoxicity in rats

    International Nuclear Information System (INIS)

    Gao Weihua; Mizukawa, Yumiko; Nakatsu, Noriyuki; Minowa, Yosuke; Yamada, Hiroshi; Ohno, Yasuo; Urushidani, Tetsuro

    2010-01-01

    systems, could be promising biomarkers for preclinical examination of hepatotoxicity.

  16. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Lake, April D. [University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ 85721 (United States); Novak, Petr [Biology Centre ASCR, Institute of Plant Molecular Biology, Ceske Budejovice 37001 (Czech Republic); Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D. [Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Co., Princeton, NJ 08543 (United States); Lu, Zhenqiang [The Arizona Statistical Consulting Laboratory, University of Arizona, Tucson, AZ 85721 (United States); Lehman-McKeeman, Lois D. [Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Co., Princeton, NJ 08543 (United States); Cherrington, Nathan J., E-mail: cherrington@pharmacy.arizona.edu [University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ 85721 (United States)

    2013-04-15

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ► Altered hepatic bile acid composition is observed in progressive NAFLD. ► Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ► Increased levels of taurine and conjugated bile acids

  17. Towards non-invasive 3D hepatotoxicity assays with optical coherence phase microscopy

    Science.gov (United States)

    Nelson, Leonard J.; Koulovasilopoulos, Andreas; Treskes, Philipp; Hayes, Peter C.; Plevris, John N.; Bagnaninchi, Pierre O.

    2015-03-01

    Three-dimensional tissue-engineered models are increasingly recognised as more physiologically-relevant than standard 2D cell culture for pre-clinical drug toxicity testing. However, many types of conventional toxicity assays are incompatible with dense 3D tissues. This study investigated the use of optical coherence phase microscopy (OCPM) as a novel approach to assess cell death in 3D tissue culture. For 3D micro-spheroid formation Human hepatic C3A cells were encapsulated in hyaluronic acid gels and cultured in 100μl MEME/10%FBS in 96-well plates. After spheroid formation the 3D liver constructs were exposed to acetaminophen on culture day 8. Acetaminophen hepatotoxicity in 3D cultures was evaluated using standard biochemical assays. An inverted OCPM in common path configuration was developed with a Callisto OCT engine (Thorlabs), centred at 930nm and a custom scanning head. Intensity data were used to perform in-depth microstructural imaging. In addition, phase fluctuations were measured by collecting several successive B scans at the same location, and statistics on the first time derivative of the phase, i.e. time fluctuations, were analysed over the acquisition time interval to retrieve overall cell viability. OCPM intensity (cell cluster size) and phase fluctuation statistics were directly compared with biochemical assays. In this study, we investigated optical coherence phase tomography to assess cell death in a 3d liver model after exposure to a prototypical hepatotoxin, acetaminophen. We showed that OCPM has the potential to assess noninvasively and label-free drug toxicity in 3D tissue models.

  18. Lycopene attenuates dichlorvos-induced oxidative damage and hepatotoxicity in rats.

    Science.gov (United States)

    El-Saad, Am Abu; Ibrahim, M M; Hazani, A A; El-Gaaly, G A

    2016-06-01

    Because of the widespread use of dichlorvos (DDVP) for domestic applications, evaluation of their toxic effects is of major concern to public health. Lycopene may lower oxidative stress by a mechanism that is not fully elucidated. The present study was undertaken to evaluate the protective efficacy of lycopene in terms of normalization of altered biochemical parameters following DDVP treatment in rats. Animals were divided into four groups. The first group was used as control, while groups 2, 3, and 4 were orally treated with lycopene (10 mg kg(-1) body weight (b.w.)), DDVP (1.6 mg kg(-1) b.w.), and DDVP plus lycopene, respectively. Results showed that oral administration of DDVP for 30 days increased the levels of lipid peroxidation markers such as malondialdehyde, 4-hydroxynonanal, and protein carbonyl content in liver. Also, a decrease in levels of vitamin C, vitamin E, and reduced glutathione was detected due to DDVP administration. These were accompanied by a decrease in the activities of antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase in the liver tissue. Moreover, DDVP increased the activities of serum transaminases, alkaline phosphatase, lactate dehydrogenase, and lipoxygenase, and the levels of bilirubin, total cholesterol, low-density lipoprotein cholesterol, triglyceride and DNA-protein crosslinks, and 8-hydroxy-2-deoxyguanosine, while decreased the level of high-density lipoprotein cholesterol. Our results provide new insights into the biochemical studies of relation between DDVP hepatotoxicity and lycopene treatment. Administration of lycopene to DDVP-treated rats reverted the status of hepatic markers to near-normal levels. These data suggest that lycopene can protect against the liver damage induced by DDVP. © The Author(s) 2015.

  19. Physiological changes due to hepatotoxicity and the protective role of some medicinal plants

    Directory of Open Access Journals (Sweden)

    Howida S. Abou Seif

    2016-06-01

    Full Text Available The liver is the largest, important organ and the site for essential biochemical reactions in the human body. It has the function to detoxify toxic substances and synthesize useful biomolecules. Therefore, damage to the liver leads to grave consequences. This damage resulted from chronic alcoholic abuse, viral hepatitis or inherited metabolic disease. Liver damage is associated with cellular necrosis, fibrosis, and increase in tissue lipid peroxidation and depletion in tissue glutathione level. Most of the hepatotoxic chemicals damage liver cells mainly by inducing lipid peroxidation and other oxidative damages in the liver. Natural antioxidants are found in many compounds classified as secondary plant metabolites, e.g. polyphenols (phenolic acids and flavonoids and terpenoids (carotenoids, and the consumption of foods that contain these compounds in large quantities seems to play an important role in prophylaxis against many diseases. Herbal medicines derived from plant extracts are being increasingly utilized to treat a wide variety of clinical disease. More attention has been paid to the protective effects of natural antioxidants against drug induced toxicities especially whenever free radical generation is involved. Popularity of herbal remedies is increasing and at least one quarter of patients with liver disease use botanicals. The World Health Organization (WHO estimates that 80 percent of the population of some Asian and African countries presently use herbal medicine for some aspect of primary health care. Some medicinal herbs have proven hepatoprotective potential. Silybum marianum (milk thistle has been used to treat liver diseases since the 16th century. Its major constituents are the flavonoids silibinin, silydianin, silychristin, and isosilibinin, of which silibinin is the biologically most active compound and used for standardization of pharmaceutical products.

  20. APOPTOTIC, HEPATOPROTECTIVE AND ANTIOXIDANT POTENTIAL OF A TRIHERBAL FORMULATION AGAINST D-GALACTOSAMINE HEPATOTOXICITY

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    Onyekachi Ogbonnaya IROANYA

    2016-12-01

    group. The data from this study suggest that GOV possess apoptotic, hepatoprotective and antioxidant activity against D-galactosamine induced hepatotoxicity in rats, thus providing scientific rationale for its use in traditional medicine for the treatment of liver diseases.

  1. Ethephon, an organophosphorous, a Fruit and Vegetable Ripener: Has potential hepatotoxic effects?

    Directory of Open Access Journals (Sweden)

    Pooja Bhadoria

    2018-01-01

    Full Text Available Introduction: In the recent years, ethephon, 2-chloroethylphosphonic acid, is one of the most commonly used plant growth regulators. At present, it is being used on fruits, vegetables, and cereals for promoting pre- and post-harvest ripening. The effect of artificial ripening has become questionable because of various health-related issues. This study was conducted to note the morphology of liver after ethephon administration as it is the site where chemicals undergo first pass metabolism and probably will be affected by ethephon. Materials and Methods: Adult Wistar albino rats were divided into experimental and control groups (10 each. Ethephon was administered at a dose of 200 mg/kg/day by a gavage tube in the experimental rats for 14 days. The animals were sacrificed within 24 h of the last dose; liver was dissected and processed for light microscopy. Hematoxylin and eosin-stained sections were studied using an image-pro express analyzer. The data obtained from control and experimental groups were statistically analyzed. Results: In the experimental rats, the body weight was found to be significantly decreased. The orderly arrangement of hepatocytes was disrupted and was replaced by blood-filled sinusoids. At sites, hepatocytes appeared to be degenerated. Councilman bodies with pyknotic nuclei and inflammatory infiltrations were seen. The population per unit area of the hepatocytes and Kupffer cells was 29.53 ± 10.65 versus 44.18 ± 10.31 and 25.12 ± 4.41versus 13.05 ± 6.5 in experimental and control groups, respectively. The decrease of hepatocytes and increase of Kupffer cells were found to be statistically significant. Conclusions: The observations in the liver are probably indicative of degenerative changes associated with ethephon. Hence, we can conclude that this plant growth regulator, Fruit and Vegetable Ripener, has hepatotoxic potential. General awareness and regarding the use of such plant growth regulators is must to reduce the

  2. Assessment of mitochondrial dysfunction-related, drug-induced hepatotoxicity in primary rat hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Cong; Sekine, Shuichi, E-mail: ssekine@faculty.chiba-u.jp; Ito, Kousei

    2016-07-01

    Evidence that mitochondrial dysfunction plays a central role in drug-induced liver injury is rapidly accumulating. In contrast to physiological conditions, in which almost all adenosine triphosphate (ATP) in hepatocytes is generated in mitochondria via aerobic respiration, the high glucose content and limited oxygen supply of conventional culture systems force primary hepatocytes to generate most ATP via cytosolic glycolysis. Thus, such anaerobically poised cells are resistant to xenobiotics that impair mitochondrial function, and are not suitable to identify drugs with mitochondrial liabilities. In this study, primary rat hepatocytes were cultured in galactose-based medium, instead of the conventional glucose-based medium, and in hyperoxia to improve the reliance of energy generation on aerobic respiration. Activation of mitochondria was verified by diminished cellular lactate release and increased oxygen consumption. These conditions improved sensitivity to the mitochondrial complex I inhibitor rotenone. Since oxidative stress is also a general cause of mitochondrial impairment, cells were exposed to test compounds in the presence of transferrin to increase the generation of reactive oxygen species via increased uptake of iron. Finally, 14 compounds with reported mitochondrial liabilities were tested to validate this new drug-induced mitochondrial toxicity assay. Overall, the culture of primary rat hepatocytes in galactose, hyperoxia and transferrin is a useful model for the identification of mitochondrial dysfunction-related drug-induced hepatotoxicity. - Highlights: • Drug-induced mitochondrial toxicity was evaluated using primary rat hepatocytes. • Galactose and hyperoxia could activate OXPHOS in primary rat hepatocytes. • Cells with enhanced OXPHOS exhibit improved sensitivity to mitochondrial toxins. • Transferrin potentiate mitochondrial toxicity via increased ROS production.

  3. Modulation of trabectedin (ET-743) hepatobiliary disposition by multidrug resistance-associated proteins (Mrps) may prevent hepatotoxicity

    International Nuclear Information System (INIS)

    Lee, Jin Kyung; Leslie, Elaine M.; Zamek-Gliszczynski, Maciej J.; Brouwer, Kim L.R.

    2008-01-01

    Trabectedin is a promising anticancer agent, but dose-limiting hepatotoxicity was observed during phase I/II clinical trials. Dexamethasone (DEX) has been shown to significantly reduce trabectedin-mediated hepatotoxicity. The current study was designed to assess the capability of sandwich-cultured primary rat hepatocytes (SCRH) to predict the hepato-protective effect of DEX against trabectedin-mediated cytotoxicity. The role of multidrug resistance-associated protein 2 (Mrp2; Abcc2) in trabectedin hepatic disposition also was examined. In SCRH from wild-type Wistar rats, cytotoxicity was observed after 24-h continuous exposure to trabectedin. SCRH pretreated with additional DEX (1 μM) exhibited a 2- to 3-fold decrease in toxicity at 100 nM and 1000 nM trabectedin. Unexpectedly, toxicity in SCRH from Mrp2-deficient (TR - ) compared to wild-type Wistar rats was markedly reduced. Depletion of glutathione from SCRH using buthionine sulfoximine (BSO) mitigated trabectedin toxicity associated with 100 nM and 1000 nM trabectedin. Western blot analysis demonstrated increased levels of CYP3A1/2 and Mrp2 in SCRH pretreated with DEX; interestingly, Mrp4 expression was increased in SCRH after BSO exposure. Trabectedin biliary recovery in isolated perfused livers from TR - rats was decreased by ∼ 75% compared to wild-type livers. In conclusion, SCRH represent a useful in vitro model to predict the hepatotoxicity of trabectedin observed in vivo. The protection by DEX against trabectedin-mediated cytotoxicity may be attributed, in part, to enhanced Mrp2 biliary excretion and increased metabolism by CYP3A1/2. Decreased trabectedin toxicity in SCRH from TR - rats, and in SCRH pretreated with BSO, may be due to increased basolateral excretion of trabectedin by Mrp3 and/or Mrp4

  4. Herb-Drug Interaction between the Traditional Hepatoprotective Formulation and Sorafenib on Hepatotoxicity, Histopathology and Pharmacokinetics in Rats

    Directory of Open Access Journals (Sweden)

    Chin-Tsung Ting

    2017-06-01

    Full Text Available Sorafenib has been used as a standard therapy for advanced hepatocellular carcinoma (HCC. In Asia, patients with HCC are potentially treated with the combination of sorafenib and Chinese herbal medicines to improve the efficiency and reduce the side effects of sorafenib. However, limited information about the herb-drug interactions is available. We hypothesize that the Chinese herbal medicine may exert hepatoprotective effects on the sorafenib-treated group. The aim of this study is to investigate the pharmacokinetic mechanism of drug-drug interactions of sorafenib including interacting with hepatoprotective formulation, Long-Dan-Xie-Gan-Tang formulation (LDXGT and with two cytochrome P450 3A4 (CYP3A4 inhibitors, grapefruit juice and ketoconazole. Liver enzyme levels and histopathology of liver slices were used to evaluate sorafenib-induced hepatotoxicity and the potential hepatoprotective effects of the LDXGT formulation on subjects treated with the combination of sorafenib and the herbal medicine. In this study, a validated HPLC-photodiode array analytical system was developed for the pharmacokinetic study of sorafenib in rats. As the result of the pharmacokinetic data, pretreatment with the LDXGT formulation did not significantly interact with sorafenib compared with sorafenib oral administration alone. Furthermore, grapefruit juice and ketoconazole did not significantly affect sorafenib metabolism. Furthermore, pretreatment with variable, single or repeat doses of the LDXGT formulation did not suppress or exacerbate the sorafenib-induced hepatotoxicity and histopathological alterations. According to these results, the LDXGT formulation is safe, but has no beneficial effects on sorafenib-induced hepatotoxicity. A detailed clinical trial should be performed to further evaluate the efficacy or adverse effects of the LDXGT formulation in combination with sorafenib in humans.

  5. Fumonisin B{sub 1} hepatotoxicity in mice is attenuated by depletion of Kupffer cells by gadolinium chloride

    Energy Technology Data Exchange (ETDEWEB)

    He, Quanren [Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389 (United States); Kim, Jiyoung [Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389 (United States); Sharma, Raghubir P [Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389 (United States)

    2005-02-01

    Fumonisin B{sub 1} (FB{sub 1}) is a toxic and carcinogenic mycotoxin produced by Fusarium verticillioides found on corn worldwide. The biological effects of FB{sub 1} are attributed to sphingolipid metabolism disruption as a result of ceramide synthase inhibition. Tumor necrosis factor {alpha} (TNF{alpha}) is an important modulator of FB{sub 1} hepatotoxicity. Kupffer cells are major source of cytokine production in liver. In the present study we investigated the effects of Kupffer cell depletion by gadolinium on FB{sub 1} hepatotoxicity in female BALB/c mice. Mice were given saline or 50 mg/kg of gadolinium chloride once via the tail vein; 16 h later they were treated with subcutaneous injections of vehicle or 2.25 mg/kg/day FB{sub 1} in saline for three successive days. Gadolinium significantly attenuated FB{sub 1}-induced increases in the activities of circulating alanine aminotransferase and aspartate aminotransferase and reduced the FB{sub 1}-induced hepatocyte apoptosis and free sphinganine accumulation in liver. Both gadolinium and FB{sub 1} treatments individually increased the expression of selected cell signal factors; e.g., TNF{alpha}, TNF receptor 1, TNF-related apoptosis-inducing ligand, lymphotoxin {beta}, interferon {gamma}, and transforming growth factor {beta}1; gadolinium chloride did not alter FB{sub 1}-induced expression of the above genes. Results indicated that Kupffer cells play a role in FB{sub 1} hepatotoxicity. Decreased FB{sub 1}-induced sphinganine accumulation and increased protective TNF{alpha} signaling by gadolinium chloride may in part account for its ameliorating effect on FB{sub 1} liver damage.

  6. Reduced hepatotoxicity by total glucosides of paeony in combination treatment with leflunomide and methotrexate for patients with active rheumatoid arthritis.

    Science.gov (United States)

    Chen, Zhu; Li, Xiang-Pei; Li, Zhi-Jun; Xu, Liang; Li, Xiao-Mei

    2013-03-01

    Combination use of methotrexate (MTX) and leflunomide (LEF) has been proved effective in the treatment of active rheumatoid arthritis (RA). However, previous trials have documented that both are associated with increased incidence of liver toxicity. As active compounds extracted from the roots of the traditional Chinese herb Paeonia lactiflora Pall, total glucosides of paeony (TGP) have been shown to have anti-inflammatory, hepatoprotective and immuno-regulatory activities, without evident toxicity or side effects. In this 24-week, open label, randomized multicenter clinical trial, we investigated the efficacy of TGP and the protective effect on hepatotoxicity in the combination treatment with LEF and MTX for patients with active RA. A total of 204 patients with active RA (DAS28>3.2) recruited from 3 regional referral centers were enrolled and received MTX and LEF combination therapy (MTX 10 mg/week plus LEF 20 mg/day) with or without TGP for up to 24 weeks by randomization. Hepatotoxicity was defined as an increase of at least 1.5-fold the upper limits of normal (ULN) of alanine aminotransferase (ALT) or aspartate aminotransferase (AST). Significantly less frequent hepatotoxicity was observed in patients with TGP than those without (9.5% vs 34.8%, p 1.5 to ≤2 times and >2 to ≤3 times the ULN were lower in TGP group than the control (1.9% vs 10.1%, 2.9% vs 12.4%, p TGP group achieved a European League Against Rheumatism (EULAR) good response or moderate response at 12 weeks, although there is no statistical significance. Similar results were observed at 24 weeks. Our preliminary study demonstrates the hepatoprotective and additive role of TGP in combination with MTX and LEF in the treatment of active RA. Copyright © 2013 Elsevier B.V. All rights reserved.

  7. A natural antioxidant, tannic acid mitigates iron-overload induced hepatotoxicity in Swiss albino mice through ROS regulation.

    Science.gov (United States)

    Basu, Tapasree; Panja, Sourav; Shendge, Anil Khushalrao; Das, Abhishek; Mandal, Nripendranath

    2018-05-01

    Tannic acid (TA), a water soluble natural polyphenol with 8 gallic acids groups, is abundantly present in various medicinal plants. Previously TA has been investigated for its antimicrobial and antifungal properties. Being a large polyphenol, TA chelates more than 1 metal. Hence TA has been explored for potent antioxidant activities against reactive oxygen species (ROS), reactive nitrogen species (RNS) and as iron chelator in vitro thereby mitigating iron-overload induced hepatotoxicity in vivo. Iron dextran was injected intraperitoneally in Swiss albino mice to induce iron-overload triggered hepatotoxicity, followed by oral administration of TA for remediation. After treatment, liver, spleen, and blood samples were processed from sacrificed animals. The liver iron, serum ferritin, serum markers, ROS, liver antioxidant status, and liver damage parameters were assessed, followed by histopathology and protein expression studies. Our results show that TA is a prominent ROS and RNS scavenger as well as iron chelator in vitro. It also reversed the ROS levels in vivo and restricted the liver damage parameters as compared to the standard drug, desirox. Moreover, this natural polyphenol exclusively ameliorates the histopathological and fibrotic changes in liver sections reducing the iron-overload, along with chelation of liver iron and normalization of serum ferritin. The protective role of TA against iron-overload induced apoptosis in liver was further supported by changed levels of caspase 3, PARP as well as Bax/BCl-2 ratio. Thus, TA can be envisaged as a better orally administrable iron chelator to reduce iron-overload induced hepatotoxicity through ROS regulation. © 2018 Wiley Periodicals, Inc.

  8. Synergistic activity of curcumin with methotrexate in ameliorating Freund's Complete Adjuvant induced arthritis with reduced hepatotoxicity in experimental animals.

    Science.gov (United States)

    Banji, David; Pinnapureddy, Jyothi; Banji, Otilia J F; Saidulu, A; Hayath, Md Sikinder

    2011-10-01

    Methotrexate is employed in low doses for the treatment of rheumatoid arthritis. One of the major drawbacks with methotrexate is hepatotoxicity resulting in poor compliance of therapy. Curcumin is an extensively used spice possessing both anti-arthritic and hepatoprotective potential. The present study was aimed at investigating the effect of curcumin (30 and 100 mg/kg) in combination with subtherapeutic dose of methotrexate (1 mg/kg) is salvaging hepatotoxicity, oxidative stress and producing synergistic anti-arthritic action with methotrexate. Wistar albino rats were induced with arthritis by subplantar injection of Freund's Complete Adjuvant and pronounced arthritis was seen after 9 days of injection. Groups of animals were treated with subtherapeutic dose of methotrexate followed half an hour later with 30 and 100mg/kg of curcumin from day 9 up to days 45 by intraperitoneal route. Methotrexate treatment in Freund's Complete Adjuvant induced arthritic animals produced elevation in the levels of aminotransferases, alkaline phosphatase, total and direct bilirubin. Enhanced oxidative stress in terms of measured lipid peroxides was observed in the methotrexate treated group. Curcumin significantly circumvented hepatotoxicity induced by methotrexate as evidenced by a change in biochemical markers possibly due to its strong anti-oxidant action. Hepatoprotective potential of curcumin was also confirmed from histological evaluation. Sub-therapeutic dose of methotrexate elicited substantial anti-arthritic action when used in combination with curcumin implying that the latter potentiated its action. Concomitant administration of curcumin with methotrexate was also found to minimize liver damage. Copyright © 2011 Elsevier B.V. All rights reserved.

  9. Fentanyl Enhances Hepatotoxicity of Paclitaxel via Inhibition of CYP3A4 and ABCB1 Transport Activity in Mice

    Science.gov (United States)

    Pan, Jia-Hao; Bi, Bing-Tian; Feng, Kun-Yao; Huang, Wan; Zeng, Wei-An

    2015-01-01

    Fentanyl, a potent opioid analgesic that is used to treat cancer pain, is commonly administered with paclitaxel in advanced tumors. However, the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanism of action is not well studied. The purpose of this study was to investigate the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanisms of action. Pharmacokinetic parameters of paclitaxel were tested using reversed phase high-performance liquid chromatography (RP-HPLC). Aspartate transaminase (AST), alanine aminotransferase (ALT), and mouse liver histopathology were examined. Moreover, the cytotoxicity of anti-carcinogens was examined using 1-(4, 5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), and the intracellular accumulation of doxorubicin and rhodamine 123 was detected by flow cytometry. Furthermore, the expression of ABCB1 and the activity of ABCB1 ATPase and CYP3A4 were also examined. In this study, the co-administration of fentanyl and paclitaxel prolonged the half-life (t1/2) of paclitaxel from 1.455 hours to 2.344 hours and decreased the clearance (CL) from 10.997 ml/h to 7.014 ml/h in mice. Fentanyl significantly increased the levels of ALT in mice to 88.2 U/L, which is more than 2-fold higher than the level detected in the control group, and it increased the histological damage in mouse livers. Furthermore, fentanyl enhanced the cytotoxicity of anti-carcinogens that are ABCB1 substrates and increased the accumulation of doxorubicin and rhodamine 123. Additionally, fentanyl stimulated ABCB1 ATPase activity and inhibited CYP3A4 activity in the liver microsomes of mice. Our study indicates that the obvious hepatotoxicity during this co-administration was due to the inhibition of CYP3A4 activity and ABCB1 transport activity. These findings suggested that the accumulation-induced hepatotoxicity of paclitaxel when it is combined with fentanyl should be avoided. PMID:26633878

  10. Analysis of changes in hepatic gene expression in a murine model of tolerance to acetaminophen hepatotoxicity (autoprotection)

    International Nuclear Information System (INIS)

    O'Connor, Meeghan A.; Koza-Taylor, Petra; Campion, Sarah N.; Aleksunes, Lauren M.; Gu, Xinsheng; Enayetallah, Ahmed E.; Lawton, Michael P.; Manautou, José E.

    2014-01-01

    Pretreatment of mice with a low hepatotoxic dose of acetaminophen (APAP) results in resistance to a subsequent, higher dose of APAP. This mouse model, termed APAP autoprotection was used here to identify differentially expressed genes and cellular pathways that could contribute to this development of resistance to hepatotoxicity. Male C57BL/6J mice were pretreated with APAP (400 mg/kg) and then challenged 48 h later with 600 mg APAP/kg. Livers were obtained 4 or 24 h later and total hepatic RNA was isolated and hybridized to Affymetrix Mouse Genome MU430 2 GeneChip. Statistically significant genes were determined and gene expression changes were also interrogated using the Causal Reasoning Engine (CRE). Extensive literature review narrowed our focus to methionine adenosyl transferase-1 alpha (MAT1A), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), flavin-containing monooxygenase 3 (Fmo3) and galectin-3 (Lgals3). Down-regulation of MAT1A could lead to decreases in S-adenosylmethionine (SAMe), which is known to protect against APAP toxicity. Nrf2 activation is expected to play a role in protective adaptation. Up-regulation of Lgals3, one of the genes supporting the Nrf2 hypothesis, can lead to suppression of apoptosis and reduced mitochondrial dysfunction. Fmo3 induction suggests the involvement of an enzyme not known to metabolize APAP in the development of tolerance to APAP toxicity. Subsequent quantitative RT-PCR and immunochemical analysis confirmed the differential expression of some of these genes in the APAP autoprotection model. In conclusion, our genomics strategy identified cellular pathways that might further explain the molecular basis for APAP autoprotection. - Highlights: • Differential expression of genes in mice resistant to acetaminophen hepatotoxicity. • Increased gene expression of Flavin-containing monooxygenase 3 and Galectin-3. • Decrease in MAT1A expression and compensatory hepatocellular regeneration. • Two distinct gene expression

  11. Comparison of hepatotoxicity and metabolism of butyltin compounds in the liver of mice, rats and guinea pigs

    Energy Technology Data Exchange (ETDEWEB)

    Ueno, Shunji; Kashimoto, Takashige; Susa, Nobuyuki; Ishii, Masamitsu; Chiba, Toshikazu [Laboratory of Veterinary Public Health, School of Veterinary Medicine and Animal Sciences, Kitasato University, Higashi 23-35-1, 034-8628, Towada-shi, Aomori (Japan); Mutoh, Ken-ichiro [Laboratory of Veterinary Anatomy, School of Veterinary Medicine and Animal Sciences, Kitasato University, Higashi 23-35-1, 034-8628, Towada-shi, Aomori (Japan); School of Veterinary Medicine and Animal Sciences, Kitasato University, Higashi 23-35-1, 034-8628, Towada-shi, Aomori (Japan); Hoshi, Fumio [Laboratory of Veterinary Anatomy, School of Veterinary Medicine and Animal Sciences, Kitasato University, Higashi 23-35-1, 034-8628, Towada-shi, Aomori (Japan); Suzuki, Takashi [Laboratory of Environmental Health and Toxicology, Kyoto Prefectural University, Hangi-cho, Shimogamo, Sakyo-ku, 606-5822, Kyoto (Japan); Sugiyama, Masayasu [Sugiyama Pharmacy, 1335-1 Shimotama, Tamagawa-cho, 759-3112, Yamaguchi (Japan)

    2003-03-01

    The hepatotoxicity of tributyltin chloride (TBTC) and dibutyltin dichloride (DBTC) was compared among mice, rats and guinea pigs in vivo. Further, the metabolism of these butyltin compounds in the liver was also investigated in these species. The oral administration of TBTC and DBTC to mice induced obvious liver injury, as demonstrated by both serodiagnosis and histopathological diagnosis. The concentrations of TBTC and DBTC that induced hepatotoxicity in mice at 24 h after oral administration were 180 and 60 {mu}mol/kg, respectively. In the case of rats, the liver injury induced by TBTC and DBTC was detected at 24 h by the serodiagnosis, but not by histopathological diagnosis. On the other hand, in guinea pigs, TBTC and DBTC administration did not produce any clear liver injury at 24 h, as evaluated by these two diagnostic methods. Thus, the following ranking was obtained with regard to increasing order of sensitivity to liver injury caused by TBTC and DBTC: mice, rats and guinea pigs. The total butyltin contents in the liver of mice were equivalent at 3 h and 24 h after the administration of TBTC or DBTC; however, the contents in the liver of rats and guinea pigs were relatively lower at 3 h and higher at 24 h than those of mice, although there were no differences between rats and guinea pigs in the total liver butyltin content. Concerning the liver metabolism of these butyltin compounds, the main form of butyltin compounds in these animals treated with TBTC was DBTC within 3 h after oral administration, while the main metabolites at 24 h were different in each species, indicating that the liver metabolism of TBTC might vary by animal type. When the animals were treated with DBTC orally, DBTC was hardly metabolized in the livers of these animals even at 24 h, and the liver levels of DBTC were two times greater in mice and guinea pigs than in rats at 3 h and were lower in mice at 24 h than in rats and guinea pigs. The analysis of cellular distributions of DBTC in

  12. Mercury-induced hepatotoxicity in zebrafish: in vivo mechanistic insights from transcriptome analysis, phenotype anchoring and targeted gene expression validation

    Directory of Open Access Journals (Sweden)

    Mathavan Sinnakaruppan

    2010-03-01

    Full Text Available Abstract Background Mercury is a prominent environmental contaminant that causes detrimental effects to human health. Although the liver has been known to be a main target organ, there is limited information on in vivo molecular mechanism of mercury-induced toxicity in the liver. By using transcriptome analysis, phenotypic anchoring and validation of targeted gene expression in zebrafish, mercury-induced hepatotoxicity was investigated and a number of perturbed cellular processes were identified and compared with those captured in the in vitro human cell line studies. Results Hepato-transcriptome analysis of mercury-exposed zebrafish revealed that the earliest deregulated genes were associated with electron transport chain, mitochondrial fatty acid beta-oxidation, nuclear receptor signaling and apoptotic pathway, followed by complement system and proteasome pathway, and thereafter DNA damage, hypoxia, Wnt signaling, fatty acid synthesis, gluconeogenesis, cell cycle and motility. Comparative meta-analysis of microarray data between zebrafish liver and human HepG2 cells exposed to mercury identified some common toxicological effects of mercury-induced hepatotoxicity in both models. Histological analyses of liver from mercury-exposed fish revealed morphological changes of liver parenchyma, decreased nucleated cell count, increased lipid vesicles, glycogen and apoptotic bodies, thus providing phenotypic evidence for anchoring of the transcriptome analysis. Validation of targeted gene expression confirmed deregulated gene-pathways from enrichment analysis. Some of these genes responding to low concentrations of mercury may serve as toxicogenomic-based markers for detection and health risk assessment of environmental mercury contaminations. Conclusion Mercury-induced hepatotoxicity was triggered by oxidative stresses, intrinsic apoptotic pathway, deregulation of nuclear receptor and kinase activities including Gsk3 that deregulates Wnt signaling

  13. Analysis of changes in hepatic gene expression in a murine model of tolerance to acetaminophen hepatotoxicity (autoprotection)

    Energy Technology Data Exchange (ETDEWEB)

    O' Connor, Meeghan A., E-mail: meeghan.oconnor@boehringer-ingelheim.com [Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092 (United States); Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877-0368 (United States); Koza-Taylor, Petra, E-mail: petra.h.koza-taylor@pfizer.com [Pfizer Inc., Groton, CT 06340 (United States); Campion, Sarah N., E-mail: sarah.campion@pfizer.com [Pfizer Inc., Groton, CT 06340 (United States); Aleksunes, Lauren M., E-mail: aleksunes@eohsi.rutgers.edu [Rutgers University, Department of Pharmacology and Toxicology, Environmental and Occupational Health Sciences Institute, Piscataway, NJ 08854 (United States); Gu, Xinsheng, E-mail: xinsheng.gu@uconn.edu [Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092 (United States); Enayetallah, Ahmed E., E-mail: ahmed.enayetallah@pfizer.com [Pfizer Inc., Groton, CT 06340 (United States); Lawton, Michael P., E-mail: michael.lawton@pfizer.com [Pfizer Inc., Groton, CT 06340 (United States); Manautou, José E., E-mail: jose.manautou@uconn.edu [Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092 (United States)

    2014-01-01

    Pretreatment of mice with a low hepatotoxic dose of acetaminophen (APAP) results in resistance to a subsequent, higher dose of APAP. This mouse model, termed APAP autoprotection was used here to identify differentially expressed genes and cellular pathways that could contribute to this development of resistance to hepatotoxicity. Male C57BL/6J mice were pretreated with APAP (400 mg/kg) and then challenged 48 h later with 600 mg APAP/kg. Livers were obtained 4 or 24 h later and total hepatic RNA was isolated and hybridized to Affymetrix Mouse Genome MU430{sub 2} GeneChip. Statistically significant genes were determined and gene expression changes were also interrogated using the Causal Reasoning Engine (CRE). Extensive literature review narrowed our focus to methionine adenosyl transferase-1 alpha (MAT1A), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), flavin-containing monooxygenase 3 (Fmo3) and galectin-3 (Lgals3). Down-regulation of MAT1A could lead to decreases in S-adenosylmethionine (SAMe), which is known to protect against APAP toxicity. Nrf2 activation is expected to play a role in protective adaptation. Up-regulation of Lgals3, one of the genes supporting the Nrf2 hypothesis, can lead to suppression of apoptosis and reduced mitochondrial dysfunction. Fmo3 induction suggests the involvement of an enzyme not known to metabolize APAP in the development of tolerance to APAP toxicity. Subsequent quantitative RT-PCR and immunochemical analysis confirmed the differential expression of some of these genes in the APAP autoprotection model. In conclusion, our genomics strategy identified cellular pathways that might further explain the molecular basis for APAP autoprotection. - Highlights: • Differential expression of genes in mice resistant to acetaminophen hepatotoxicity. • Increased gene expression of Flavin-containing monooxygenase 3 and Galectin-3. • Decrease in MAT1A expression and compensatory hepatocellular regeneration. • Two distinct gene

  14. Acute liver failure in a term neonate after repeated paracetamol administration

    OpenAIRE

    Bucaretchi, Fabio; Fernandes, Carla Borrasca; Branco, Maira Migliari; Capitani, Eduardo Mello De; Hyslop, Stephen; Caldas, Jamil Pedro S.; Moreno, Carolina Araujo; Porta, Gilda

    2014-01-01

    Objective: Severe hepatotoxicity caused by paracetamol is rare in neonates. We report a case of paracetamol-induced acute liver failure in a term neonate. Case description: A 26-day-old boy was admitted with intestinal bleeding, shock signs, slight liver enlargement, coagulopathy, metabolic acidosis (pH=7.21; bicarbonate: 7.1mEq/L), hypoglycemia (18mg/dL), increased serum aminotransferase activity (AST=4,039IU/L; ALT=1,087IU/L) and hyperbilirubinemia (total: 9.57mg/dL; direct: 6.18mg/dL)...

  15. Acute nephritic syndrome

    Science.gov (United States)

    Glomerulonephritis - acute; Acute glomerulonephritis; Nephritis syndrome - acute ... Acute nephritic syndrome is often caused by an immune response triggered by an infection or other disease. Common causes in children ...

  16. Albendazole Induced Recurrent Acute Toxic Hepatitis: A Case Report.

    Science.gov (United States)

    Bilgic, Yilmaz; Yilmaz, Cengiz; Cagin, Yasir Furkan; Atayan, Yahya; Karadag, Nese; Harputluoglu, Murat Muhsin Muhip

    2017-01-01

    Drug induced acute toxic hepatitis can be idiosyncratic. Albendazole, a widely used broad spectrum antiparasitic drug is generally accepted as a safe drug. It may cause asymptomatic transient liver enzyme abnormalities but acute toxic hepatitis is very rare. Case Report : Herein, we present the case of 47 year old woman with recurrent acute toxic hepatitis after a single intake of albendazole in 2010 and 2014. The patient was presented with symptoms and findings of anorexia, vomiting and jaundice. For diagnosis, other acute hepatitis etiologies were excluded. Roussel Uclaf Causality Assessment Method (RUCAM) score was calculated and found to be 10, which meant highly probable drug hepatotoxicity. Within 2 months, all pathological findings came to normal. There are a few reported cases of albendazole induced toxic hepatitis, but at adults, there is no known recurrent acute toxic hepatitis due to albendazole at this certainty according to RUCAM score. Physicians should be aware of this rare and potentially fatal adverse effect of albendazole. © Acta Gastro-Enterologica Belgica.

  17. Repeated dose studies with pure Epigallocatechin-3-gallate demonstrated dose and route dependant hepatotoxicity with associated dyslipidemia.

    Science.gov (United States)

    Ramachandran, Balaji; Jayavelu, Subramani; Murhekar, Kanchan; Rajkumar, Thangarajan

    2016-01-01

    EGCG (Epigallocatechin-3-gallate) is the major active principle catechin found in green tea. Skepticism regarding the safety of consuming EGCG is gaining attention, despite the fact that it is widely being touted for its potential health benefits, including anti-cancer properties. The lack of scientific data on safe dose levels of pure EGCG is of concern, while EGCG has been commonly studied as a component of GTE (Green tea extract) and not as a single active constituent. This study has been carried out to estimate the maximum tolerated non-toxic dose of pure EGCG and to identify the treatment related risk factors. In a fourteen day consecutive treatment, two different administration modalities were compared, offering an improved [i.p (intraperitoneal)] and limited [p.o (oral)] bioavailability. A trend of dose and route dependant hepatotoxicity was observed particularly with i.p treatment and EGCG increased serum lipid profile in parallel to hepatotoxicity. Fourteen day tolerable dose of EGCG was established as 21.1 mg/kg for i.p and 67.8 mg/kg for p.o. We also observed that, EGCG induced effects by both treatment routes are reversible, subsequent to an observation period for further fourteen days after cessation of treatment. It was demonstrated that the severity of EGCG induced toxicity appears to be a function of dose, route of administration and period of treatment.

  18. Alleviative effects of s-allyl cysteine and s-ethyl cysteine on MCD diet-induced hepatotoxicity in mice.

    Science.gov (United States)

    Lin, Chun-che; Yin, Mei-chin; Liu, Wen-hu

    2008-11-01

    Alleviative effects of s-allyl cysteine (SAC) and s-ethyl cysteine (SEC) upon methionine and choline deficient (MCD) diet-induced hepatotoxicity in mice were examined. SAC or SEC at 1g/L was added into drinking water for 7 weeks with MCD diet. MCD feeding significantly increased hepatic triglyceride and cholesterol levels, and elevated the activity of glucose-6-phosphate dehydrogenase (G6PDH), malic enzyme, fatty acid synthase (FAS) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (P MCD feeding significantly lowered serum and hepatic glutathione (GSH) levels, increased malondialdehyde (MDA) and oxidized glutathione (GSSG) formation, and suppressed the activity and mRNA expression of glutathione peroxidase (GPX), superoxide dismutase (SOD) and catalase (P MCD feeding significantly enhanced the mRNA expression of interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, matrix metalloproteinases-9 (MMP-9) and collagen-alpha1 (P MCD-induced hepatotoxicity.

  19. Taurine zinc solid dispersions attenuate doxorubicin-induced hepatotoxicity and cardiotoxicity in rats

    International Nuclear Information System (INIS)

    Wang, Yu; Mei, Xueting; Yuan, Jingquan; Lu, Wenping; Li, Binglong; Xu, Donghui

    2015-01-01

    Dissolution of taurine zinc complex can be increased by solid dispersions (SDs). • Taurine zinc SDs blocked doxorubicin-induced hepatotoxicity and cardiotoxicity. • Taurine zinc SDs can alleviate oxidative stress and dampen JNK phosphorylation. • Taurine zinc SDs increased the expression of UGT, HO-1 at mRNA and protein level. • Taurine zinc SDs revealed greater hepatoprotective effects than silymarin.

  20. Taurine zinc solid dispersions attenuate doxorubicin-induced hepatotoxicity and cardiotoxicity in rats

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yu; Mei, Xueting; Yuan, Jingquan; Lu, Wenping; Li, Binglong; Xu, Donghui, E-mail: Donghuixu007@163.com

    2015-11-15

    Dissolution of taurine zinc complex can be increased by solid dispersions (SDs). • Taurine zinc SDs blocked doxorubicin-induced hepatotoxicity and cardiotoxicity. • Taurine zinc SDs can alleviate oxidative stress and dampen JNK phosphorylation. • Taurine zinc SDs increased the expression of UGT, HO-1 at mRNA and protein level. • Taurine zinc SDs revealed greater hepatoprotective effects than silymarin.

  1. Ethephon, an organophosphorus, a fruit and vegetable ripener: Has potential hepatotoxic effects.

    Directory of Open Access Journals (Sweden)

    Pooja Bhadoria

    2015-01-01

    serious hepatotoxic potential. Thus a habit of thorough cleaning and washing of fruits and vegetables, before consumption, should be adopted to prevent the ingestion of this potential hepatotoxin.

  2. Possible Protective Effect of Low-dose Gamma Irradiation and Certain Natural Products on Chemically Induced Hepatotoxicity in Rats

    International Nuclear Information System (INIS)

    Rashed, R.R.A.

    2015-01-01

    Liver, the largest organ in the human body, is a vital organ that performs more than 500 vital metabolic functions. More than a 1000 drugs of the modern pharmacopoeia can induce liver injury with different clinical presentations. In the most severe cases, drug-induced liver injury may require liver transplantation or lead to death of the patient. Acetaminophen (acetyl-para-amino-phenol, paracetamol, APAP) is safe at therapeutic doses, but accidental or intentional overdose can induce severe hepatotoxicity in both humans and experimental animals. APAP-induced hepatotoxicity is dose related and reproducible in animals, and is thus widely used as a model for experimentally induced hepatotoxicity. Many herbs have been used as natural remedies for the prevention and/or treatment of liver diseases. Herbal drugs gained importance and popularity in recent years because of their safety, efficacy and cost effectiveness. Interestingly, exposure to a small dose or dose rate of radiation was reported to induce stress, perturbing homeostasis. Organisms respond adaptively to such disturbances. The mechanisms by which low-dose radiation (LDR) protects the cells or tissue against subsequent radiation- or drug-induced toxicities have been attributed to its stimulation of various protective molecules such as antioxidants and anti apoptotic. In the light of the above mentioned information, this study was constructed in order to investigate the mechanism(s) of the hepato protective effects offered by each of garlic oil (GO), black seed oil (BO) and sesame oil (SO) each alone or combined with low dose total body gamma (γ)-irradiation against APAP-induced hepatotoxicity in male albino Wistar rats. Preliminary pilot studies were performed prior to the main experimental work; in order to select the effective irradiation dose, the hepato protective natural products and the duration of their administration to be used in the main study. To carry out the main study, 96 rats were randomly

  3. Acute Pancreatitis and Pregnancy

    Science.gov (United States)

    ... Pancreatitis Acute Pancreatitis and Pregnancy Acute Pancreatitis and Pregnancy Timothy Gardner, MD Acute pancreatitis is defined as ... pancreatitis in pregnancy. Reasons for Acute Pancreatitis and Pregnancy While acute pancreatitis is responsible for almost 1 ...

  4. Predictivity of dog co-culture model, primary human hepatocytes and HepG2 cells for the detection of hepatotoxic drugs in humans

    International Nuclear Information System (INIS)

    Atienzar, Franck A.; Novik, Eric I.; Gerets, Helga H.; Parekh, Amit; Delatour, Claude; Cardenas, Alvaro; MacDonald, James; Yarmush, Martin L.; Dhalluin, Stéphane

    2014-01-01

    Drug Induced Liver Injury (DILI) is a major cause of attrition during early and late stage drug development. Consequently, there is a need to develop better in vitro primary hepatocyte models from different species for predicting hepatotoxicity in both animals and humans early in drug development. Dog is often chosen as the non-rodent species for toxicology studies. Unfortunately, dog in vitro models allowing long term cultures are not available. The objective of the present manuscript is to describe the development of a co-culture dog model for predicting hepatotoxic drugs in humans and to compare the predictivity of the canine model along with primary human hepatocytes and HepG2 cells. After rigorous optimization, the dog co-culture model displayed metabolic capacities that were maintained up to 2 weeks which indicates that such model could be also used for long term metabolism studies. Most of the human hepatotoxic drugs were detected with a sensitivity of approximately 80% (n = 40) for the three cellular models. Nevertheless, the specificity was low approximately 40% for the HepG2 cells and hepatocytes compared to 72.7% for the canine model (n = 11). Furthermore, the dog co-culture model showed a higher superiority for the classification of 5 pairs of close structural analogs with different DILI concerns in comparison to both human cellular models. Finally, the reproducibility of the canine system was also satisfactory with a coefficient of correlation of 75.2% (n = 14). Overall, the present manuscript indicates that the dog co-culture model may represent a relevant tool to perform chronic hepatotoxicity and metabolism studies. - Highlights: • Importance of species differences in drug development. • Relevance of dog co-culture model for metabolism and toxicology studies. • Hepatotoxicity: higher predictivity of dog co-culture vs HepG2 and human hepatocytes

  5. Computed tomography of the brain, hepatotoxic drugs and high alcohol consumption in male alcoholic patients and a random sample from the general male population

    Energy Technology Data Exchange (ETDEWEB)

    Muetzell, S. (Univ. Hospital of Uppsala (Sweden). Dept. of Family Medicine)

    1992-01-01

    Computed tomography (CT) of the brain was performed in a random sample of a total of 195 men and 211 male alcoholic patients admitted for the first time during a period of two years from the same geographically limited area of Greater Stockholm as the sample. Laboratory tests were performed, including liver and pancreatic tests. Toxicological screening was performed and the consumption of hepatotoxic drugs was also investigated. The groups were then subdivided with respect to alcohol consumption and use of hepatotoxic drugs: group IA, men from the random sample with low or moderate alcohol consumption and no use of hepatotoxic drugs; IB, men from the random sample with low or moderate alcohol consumption with use of hepatotoxic drugs; IIA, alcoholic inpatients with use of alcohol and no drugs; and IIB, alcoholic inpatients with use of alcohol and drugs. Group IIB was found to have a higher incidence of cortical and subcortical changes than group IA. Group IB had a higher incidence of subcortical changes than group IA, and they differed only in drug use. Groups IIN and IIA only differed in drug use, and IIB had a higher incidence of brian damage except for anterior horn index and wide cerebellar sulci indicating vermian atrophy. Significantly higher serum levels of bilirubin, GGT, ASAT, ALAT, CK LD, and amylase were found in IIB. The results indicate that drug use influences the incidence of cortical and subcortical aberrations, except anterior horn index. It is concluded that the groups with alcohol abuse who used hepatotoxic drugs showed a picture of cortical changes (wide transport sulci and clear-cut of high-grade cortical changes) and also of subcortical aberrations, expressed as an increased widening on the third ventricle.

  6. Computed tomography of the brain, hepatotoxic drugs and high alcohol consumption in male alcoholic patients and a random sample from the general male population

    International Nuclear Information System (INIS)

    Muetzell, S.

    1992-01-01

    Computed tomography (CT) of the brain was performed in a random sample of a total of 195 men and 211 male alcoholic patients admitted for the first time during a period of two years from the same geographically limited area of Greater Stockholm as the sample. Laboratory tests were performed, including liver and pancreatic tests. Toxicological screening was performed and the consumption of hepatotoxic drugs was also investigated. The groups were then subdivided with respect to alcohol consumption and use of hepatotoxic drugs: group IA, men from the random sample with low or moderate alcohol consumption and no use of hepatotoxic drugs; IB, men from the random sample with low or moderate alcohol consumption with use of hepatotoxic drugs; IIA, alcoholic inpatients with use of alcohol and no drugs; and IIB, alcoholic inpatients with use of alcohol and drugs. Group IIB was found to have a higher incidence of cortical and subcortical changes than group IA. Group IB had a higher incidence of subcortical changes than group IA, and they differed only in drug use. Groups IIN and IIA only differed in drug use, and IIB had a higher incidence of brian damage except for anterior horn index and wide cerebellar sulci indicating vermian atrophy. Significantly higher serum levels of bilirubin, GGT, ASAT, ALAT, CK LD, and amylase were found in IIB. The results indicate that drug use influences the incidence of cortical and subcortical aberrations, except anterior horn index. It is concluded that the groups with alcohol abuse who used hepatotoxic drugs showed a picture of cortical changes (wide transport sulci and clear-cut of high-grade cortical changes) and also of subcortical aberrations, expressed as an increased widening on the third ventricle

  7. Predictivity of dog co-culture model, primary human hepatocytes and HepG2 cells for the detection of hepatotoxic drugs in humans

    Energy Technology Data Exchange (ETDEWEB)

    Atienzar, Franck A., E-mail: franck.atienzar@ucb.com [UCB Pharma SA, Non-Clinical Development, Chemin du Foriest, 1420 Braine-l' Alleud (Belgium); Novik, Eric I. [H mu rel Corporation, 675 U.S. Highway 1, North Brunswick, NJ 08902 (United States); Gerets, Helga H. [UCB Pharma SA, Non-Clinical Development, Chemin du Foriest, 1420 Braine-l' Alleud (Belgium); Parekh, Amit [H mu rel Corporation, 675 U.S. Highway 1, North Brunswick, NJ 08902 (United States); Delatour, Claude; Cardenas, Alvaro [UCB Pharma SA, Non-Clinical Development, Chemin du Foriest, 1420 Braine-l' Alleud (Belgium); MacDonald, James [Chrysalis Pharma Consulting, LLC, 385 Route 24, Suite 1G, Chester, NJ 07930 (United States); Yarmush, Martin L. [Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854 (United States); Dhalluin, Stéphane [UCB Pharma SA, Non-Clinical Development, Chemin du Foriest, 1420 Braine-l' Alleud (Belgium)

    2014-02-15

    Drug Induced Liver Injury (DILI) is a major cause of attrition during early and late stage drug development. Consequently, there is a need to develop better in vitro primary hepatocyte models from different species for predicting hepatotoxicity in both animals and humans early in drug development. Dog is often chosen as the non-rodent species for toxicology studies. Unfortunately, dog in vitro models allowing long term cultures are not available. The objective of the present manuscript is to describe the development of a co-culture dog model for predicting hepatotoxic drugs in humans and to compare the predictivity of the canine model along with primary human hepatocytes and HepG2 cells. After rigorous optimization, the dog co-culture model displayed metabolic capacities that were maintained up to 2 weeks which indicates that such model could be also used for long term metabolism studies. Most of the human hepatotoxic drugs were detected with a sensitivity of approximately 80% (n = 40) for the three cellular models. Nevertheless, the specificity was low approximately 40% for the HepG2 cells and hepatocytes compared to 72.7% for the canine model (n = 11). Furthermore, the dog co-culture model showed a higher superiority for the classification of 5 pairs of close structural analogs with different DILI concerns in comparison to both human cellular models. Finally, the reproducibility of the canine system was also satisfactory with a coefficient of correlation of 75.2% (n = 14). Overall, the present manuscript indicates that the dog co-culture model may represent a relevant tool to perform chronic hepatotoxicity and metabolism studies. - Highlights: • Importance of species differences in drug development. • Relevance of dog co-culture model for metabolism and toxicology studies. • Hepatotoxicity: higher predictivity of dog co-culture vs HepG2 and human hepatocytes.

  8. The enhanced atorvastatin hepatotoxicity in diabetic rats was partly attributed to the upregulated hepatic Cyp3a and SLCO1B1

    Science.gov (United States)

    Shu, Nan; Hu, Mengyue; Ling, Zhaoli; Liu, Peihua; Wang, Fan; Xu, Ping; Zhong, Zeyu; Sun, Binbin; Zhang, Mian; Li, Feng; Xie, Qiushi; Liu, Xiaodong; Liu, Li

    2016-01-01

    Liver injury is a common adverse effect of atorvastatin. This study aimed to investigate atorvastatin-induced hepatotoxicity in diabetic rats induced by high-fat diet combined with streptozotocin. The results showed that 40 mg/kg atorvastatin was lethal to diabetic rats, whose mean survival time was 6.2 days. Severe liver injury also occurred in diabetic rats treated with 10 mg/kg and 20 mg/kg atorvastatin. The in vitro results indicated that atorvastatin cytotoxicity in hepatocytes of diabetic rats was more severe than normal and high-fat diet feeding rats. Expressions and activities of hepatic Cyp3a and SLCO1B1 were increased in diabetic rats, which were highly correlated with hepatotoxicity. Antioxidants (glutathione and N-Acetylcysteine), Cyp3a inhibitor ketoconazole and SLCO1B1 inhibitor gemfibrozil suppressed cytotoxicity and ROS formation in primary hepatocytes of diabetic rats. In HepG2 cells, up-regulations of CYP3A4 and SLCO1B1 potentiated hepatotoxicity and ROS generation, whereas knockdowns of CYP3A4 and SLCO1B1 as well as CYP3A4/SLCO1B1 inhibitions showed the opposite effects. Phenobarbital pretreatment was used to induce hepatic Cyp3a and SLCO1B1 in rats. Phenobarbital aggravated atorvastatin-induced hepatotoxicity, while decreased plasma exposure of atorvastatin. All these findings demonstrated that the upregulations of hepatic Cyp3a and SLCO1B1 in diabetic rats potentiated atorvastatin-induced hepatotoxicity via increasing ROS formation. PMID:27624558

  9. Abrogation of cisplatin-induced hepatotoxicity in mice by xanthorrhizol is related to its effect on the regulation of gene transcription

    International Nuclear Information System (INIS)

    Hwan Kim, Seong; Ok Hong, Kyoung; Chung, Won-Yoon; Kwan Hwang, Jae; Park, Kwang-Kyun

    2004-01-01

    Cisplatin is a widely used anticancer drug, but at high dose, it can produce undesirable side effects such as hepatotoxicity. Because Curcuma xanthorrhiza Roxb. (Zingiberaceae) has been traditionally used to treat liver disorders, the protective effect of xanthorrhizol, which is isolated from C. xanthorrhiza, on cisplatin-induced hepatotoxicity was evaluated in mice. The pretreatment of xanthorrhizol (200 mg/kg/day, po) for 4 days prevented the hepatotoxicity induced by cisplatin (45 mg/kg, ip) with statistical significance. Interestingly, it abrogated cisplatin-induced DNA-binding activity of nuclear factor-kappaB (NF-κB), which consequently affected mRNA expression levels of NF-κB-dependent genes, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), even in part. It also attenuated the cisplatin-suppressed DNA-binding activity of activator protein 1 (AP-1). Using differential display reverse transcription-polymerase chain reaction (DDRT-PCR), seven upregulated genes including S100 calcium binding protein A9 (S100A9) mRNA and antigenic determinant for rec-A protein mRNA and five downregulated genes including caseinolytic protease X (ClpX) mRNA and ceruloplasmin (CP) mRNA by cisplatin were identified. Although these mRNA expression patterns were not totally consistent with gel shift patterns, altered expression levels by cisplatin were reversed by the pretreatment of xanthorrhizol. In conclusion, the ability of xanthorrhizol to regulate the DNA-binding activities of transcription factors, NF-κB and AP-1, could be one possible mechanism to elucidate the preventive effect of xanthorrhizol on cisplatin-induced hepatotoxicity. Furthermore, genes identified in this study could be helpful to understand the mechanism of cisplatin-induced hepatotoxicity. Finally, the combination treatment of xanthorrhizol and cisplatin may provide more advantage than single treatment of cisplatin in cancer therapy

  10. Anti-inflammatory effects and hepatotoxicity of Tripterygium-loaded solid lipid nanoparticles on adjuvant-induced arthritis in rats.

    Science.gov (United States)

    Xue, Mei; Jiang, Zhen-zhou; Wu, Tao; Li, Ji; Zhang, Liang; Zhao, Yan; Li, Xue-jun; Zhang, Lu-Yong; Yang, Shu-yu

    2012-08-15

    Tripterygium wilfordii Hook f. (TWHF) has been demonstrated to have anti-inflammatory, immunosuppressive effects and its clinical use was restricted to some extent due to some toxic effects on the digestive, urogenital, and blood circulatory systems, especially the male reproductive system. In the previous study, we had confirmed that TWHF-loaded solid lipid nanoparticles (SLN) have protective effects on male reproductive toxicity in rats. Anti-inflammatory effects and hepatotoxicity of TWHF-SLN remain to be unidentified. The present study was focused on the anti-inflammatory effect of complete Freund's adjuvant-induced arthritis in rats treated with TWHF-SLN as well as the effects of SLN delivery system on decreasing the hepatotoxicity induced by tripterygium. Sixty-four healthy male rats were randomly divided into eight groups with eight rats each. From day 18 after FCA injection, TWHF-SLN group (120, 60, 30 mg/kg) and TWHF group (120, 60, 30 mg/kg) were administered by oral gavage for 24 consecutive days. The control group was with saline and model control group was without any treatment. The volume of the right hind paws was evaluated at 0, 4, 8, 12, 18, 24, 30, 36 and 42 days post-injection of FCA by a home-made connected device. The serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), total bilirubin (TBIL) and albumin (ALB) levels were evaluated by an autoanalyzer. Activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) malondialdehyde (MDA) and xanthine oxidase (XOD) levels were determined using commercial kits. The PG level in sera was examined by double antibody sandwich method. Tissue histopathology was evaluated with hematoxylin and eosin (H&E). The results show that TWHF-SLN can significantly reduce rat paw volume at 60 mg/kg (psystem can enhance the anti-inflammatory activity of TWHF, and meanwhile has a protective effect against TWHF

  11. Investigating the CYP2E1 Potential Role in the Mechanisms Behind INH/LPS-Induced Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Hozeifa M. Hassan

    2018-03-01

    Full Text Available Tuberculosis (TB is one of the oldest infectious diseases that affected humankind and remains one of the world’s deadliest communicable diseases that could be considered as global emergency, but the discovery and development of isoniazid (INH in the 1950s paved the way to an effective single and/or combined first-line anti-TB therapy. However, administration of INH induces severe hepatic toxicity in some patients. Previously, we establish a rat model of INH hepatotoxicity utilizing the inflammatory stress theory, in which bacterial lipopolysaccharide (LPS potentially enhanced INH toxicity. These enhancing activities ranged between augmenting the inflammatory stress, oxidative stress, alteration of bile acid homeostasis, and CYP2E1 over-expression. Although pre-treatment with dexamethasone (DEX helped overcome both inflammatory and oxidative stress which ended-up in alleviation of LPS augmenting effects, but still minor toxicities were being detected, alongside with CYP2E1 over expression. This finding positively indicated the corner-stone role played by CYP2E1 in the pathogenesis of INH/LPS-induced liver damage. Therefore, we examined whether INH/LPS co-treatment with CYP2E1 inhibitor diallyl sulfide (DAS and DEX can protect against the INH/LPS-induced hepatotoxicity. Our results showed that pre-administration of both DAS and DEX caused significant reduction in serum TBA, TBil, and gamma-glutamyl transferase levels. Furthermore, the histopathological analysis showed that DAS and DEX could effectively reverse the liver lesions seen following INH/LPS treatment and protect against hepatic steatosis as indicated by absence of lipid accumulation. Pre-treatment with DAS alone could not completely block the CYP2E1 protein expression following INH/LPS treatment, as appeared in the immunoblotting and immunohistochemistry results. This is probably due to the fact that the combined enhancement activities of both INH and LPS on CYP2E1 protein expression

  12. Acute pancreatitis.

    Science.gov (United States)

    Talukdar, Rupjyoti; Vege, Santhi S

    2015-09-01

    To summarize recent data on classification systems, cause, risk factors, severity prediction, nutrition, and drug treatment of acute pancreatitis. Comparison of the Revised Atlanta Classification and Determinant Based Classification has shown heterogeneous results. Simvastatin has a protective effect against acute pancreatitis. Young black male, alcohol, smoldering symptoms, and subsequent diagnosis of chronic pancreatitis are risk factors associated with readmissions after acute pancreatitis. A reliable clinical or laboratory marker or a scoring system to predict severity is lacking. The PYTHON trial has shown that oral feeding with on demand nasoenteric tube feeding after 72 h is as good as nasoenteric tube feeding within 24 h in preventing infections in predicted severe acute pancreatitis. Male sex, multiple organ failure, extent of pancreatic necrosis, and heterogeneous collection are factors associated with failure of percutaneous drainage of pancreatic collections. The newly proposed classification systems of acute pancreatitis need to be evaluated more critically. New biomarkers are needed for severity prediction. Further well designed studies are required to assess the type of enteral nutritional formulations for acute pancreatitis. The optimal minimally invasive method or combination to debride the necrotic collections is evolving. There is a great need for a drug to treat the disease early on to prevent morbidity and mortality.

  13. TRPV1 in brain is involved in acetaminophen-induced antinociception.

    Directory of Open Access Journals (Sweden)

    Christophe Mallet

    2010-09-01

    Full Text Available Acetaminophen, the major active metabolite of acetanilide in man, has become one of the most popular over-the-counter analgesic and antipyretic agents, consumed by millions of people daily. However, its mechanism of action is still a matter of debate. We have previously shown that acetaminophen is further metabolized to N-(4-hydroxyphenyl-5Z,8Z,11Z,14Z -eicosatetraenamide (AM404 by fatty acid amide hydrolase (FAAH in the rat and mouse brain and that this metabolite is a potent activator of transient receptor potential vanilloid 1 (TRPV(1 in vitro. Pharmacological activation of TRPV(1 in the midbrain periaqueductal gray elicits antinociception in rats. It is therefore possible that activation of TRPV(1 in the brain contributes to the analgesic effect of acetaminophen.Here we show that the antinociceptive effect of acetaminophen at an oral dose lacking hypolocomotor activity is absent in FAAH and TRPV(1 knockout mice in the formalin, tail immersion and von Frey tests. This dose of acetaminophen did not affect the global brain contents of prostaglandin E(2 (PGE(2 and endocannabinoids. Intracerebroventricular injection of AM404 produced a TRPV(1-mediated antinociceptive effect in the mouse formalin test. Pharmacological inhibition of TRPV(1 in the brain by intracerebroventricular capsazepine injection abolished the antinociceptive effect of oral acetaminophen in the same test.This study shows that TRPV(1 in brain is involved in the antinociceptive action of acetaminophen and provides a strategy for developing central nervous system active oral analgesics based on the coexpression of FAAH and TRPV(1 in the brain.

  14. Diazinon-induced hepatotoxicity and protective effect of vitamin E on some biochemical indices and ultrastructural changes

    International Nuclear Information System (INIS)

    Kalender, Suna; Ogutcu, Ayse; Uzunhisarcikli, Meltem; Acikgoz, Fatma; Durak, Dilek; Ulusoy, Yavuz; Kalender, Yusuf

    2005-01-01

    Diazinon, an organophosphate insecticide has been used in agriculture and domestic for several years. The aim of present study was to analyze the hepatotoxic effect of diazinon which caused biochemical and ultrastructural changes in adult male Wistar rats and to evaluate the possible protective effect of vitamin E. Vitamin E (200 mg/kg, twice a week), diazinon (10 mg/kg per day, once a day in corn oil) and vitamin E (200 mg/kg, twice a week) + diazinon (10 mg/kg per day, once a day in corn oil) combination were given to rats (n = 8) orally via gavage for 7 weeks. Biochemical indices in serum [total protein, albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol, triglyceride and low density lipoprotein cholesterol (VLDL-cholesterol)] and ultrastructural changes were investigated at the end of the 1st, 4th and 7th weeks comparatively with control group (n = 8). It was observed that; at the end of 1st week, there was a statistically significance in all parameters except total protein and albumin, and at the end of 4th and 7th weeks, there was a statistically significance in all parameters when diazinon-treated group compared to control group (P < 0.01). At the end of 1st week, ALP, ALT, total cholesterol and triglyceride, at the end of 4th week, all parameters except VLDL-cholesterol, at the end of 7th week, all parameters were statistically significant when vitamin E + diazinon-treated group compared with diazinon-treated group (P < 0.01). In our electron microscopic investigations, while swelling of mitochondria and breaking up of the mitochondrial cristae of hepatocytes in diazinon-treated groups were observing, no pathological findings were observed in vitamin E + diazinon-treated groups. We conclude that vitamin E decreases diazinon hepatotoxicity, but vitamin E does not protect completely

  15. Anti-hepatotoxic activities of Hibiscus sabdariffa L. in animal model of streptozotocin diabetes-induced liver damage.

    Science.gov (United States)

    Adeyemi, David O; Ukwenya, Victor O; Obuotor, Efere M; Adewole, Stephen O

    2014-07-30

    Flavonoid-rich aqueous fraction of methanolic extract of Hibiscus sabdariffa calyx was evaluated for its anti-hepatotoxic activities in streptozotocin-induced diabetic Wistar rats. Diabetes Mellitus was induced in Wistar rats by a single i.p injection of 80 mg/kg b.w. streptozotocin (STZ) dissolved in 0.1 M citrate buffer (pH 6.3). The ameliorative effects of the extract on STZ-diabetes induced liver damage was evident from the histopathological analysis and the biochemical parameters evaluated in the serum and liver homogenates. Reduced levels of glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) (3.76 ± 0.38 μM, 0.42 ± 0.04 U/L, 41.08 ± 3.04 U/ml, 0.82 ± 0.04 U/L respectively) in the liver of diabetic rats were restored to a near normal level in the Hibiscus sabdariffa-treated rats (6.87 ± 0.51 μM, 0.72 ± 0.06 U/L, 87.92 ± 5.26 U/ml, 1.37 ± 0.06 U/L respectively). Elevated levels of aspartate amino transferase (AST), alanine amino transferase (ALT) and alkaline phosphatase (ALP) in the serum of diabetic rats were also restored in Hibiscus sabdariffa -treated rats. Examination of stained liver sections revealed hepatic fibrosis and excessive glycogen deposition in the diabetic rats. These pathological changes were ameliorated in the extract-treated rats. The anti-hepatotoxic activity of Hibiscus sabdariffa extract in STZ diabetic rats could be partly related to its antioxidant activity and the presence of flavonnoids.

  16. Assessment of hepatotoxic and nephrotoxic effects of occupational exposure to unleaded gasoline: A study in shiraz petrol stations

    Directory of Open Access Journals (Sweden)

    M. Neghab

    2014-09-01

    Full Text Available Introduction: Gasoline is a complex mixture of more than 500 various hydrocarbons. The elimination of lead from petrol has been associated with the production of significant amounts of hepatotoxic and nephrotoxic monocyclic aromatic hydrocarbons such as benzene, toluene and xylene (BTX. The main purpose of this study was to ascertain whether or not exposure to unleaded petrol, under normal working conditions, is associated with any hepatotoxic or nephrotoxic response. .Materials and Methods: This was a retrospective cohort study in which 200 subjects with current exposure to unleaded petrol working in Shiraz petrol stations as well as 200 unexposed employees were investigated. Using standard methods, atmospheric concentrations of BTX were measured. Additionally, blood and urine samples were taken from subjects for routine biochemical tests of kidney and liver function. .Results: The geometric means of airborne concentrations of BTX were found to be 0.24, 0.37 and 0.64 ppm, respectively. The result of blood chemistry tests showed that means of direct bilirubin, ALT, AST, urea and plasma creatinine were significantly higher in exposed subjects than in unexposed employees, although all of these parameters were in the normal range. Conversely, serum albumin, total protein and serum concentration of calcium and sodium were significantly lower in petrol station workers than in their unexposed counterparts. .Conclusions: The average exposure of petrol station workers to BTX is lower than the current TLVs for these chemicals. However, clinical significance and long-term results of observed changes in liner and kidney of exposed workers needs more evident in comparison with unexposed group.

  17. Repeated dose studies with pure Epigallocatechin-3-gallate demonstrated dose and route dependant hepatotoxicity with associated dyslipidemia

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    Balaji Ramachandran

    Full Text Available EGCG (Epigallocatechin-3-gallate is the major active principle catechin found in green tea. Skepticism regarding the safety of consuming EGCG is gaining attention, despite the fact that it is widely being touted for its potential health benefits, including anti-cancer properties. The lack of scientific data on safe dose levels of pure EGCG is of concern, while EGCG has been commonly studied as a component of GTE (Green tea extract and not as a single active constituent. This study has been carried out to estimate the maximum tolerated non-toxic dose of pure EGCG and to identify the treatment related risk factors. In a fourteen day consecutive treatment, two different administration modalities were compared, offering an improved [i.p (intraperitoneal] and limited [p.o (oral] bioavailability. A trend of dose and route dependant hepatotoxicity was observed particularly with i.p treatment and EGCG increased serum lipid profile in parallel to hepatotoxicity. Fourteen day tolerable dose of EGCG was established as 21.1 mg/kg for i.p and 67.8 mg/kg for p.o. We also observed that, EGCG induced effects by both treatment routes are reversible, subsequent to an observation period for further fourteen days after cessation of treatment. It was demonstrated that the severity of EGCG induced toxicity appears to be a function of dose, route of administration and period of treatment. Keywords: EGCG, Green tea, Serum lipids, Dose dependant toxicity, Route dependant toxicity, Liver toxicity, Dyslipidemia

  18. The protective potential and possible mechanism of Phyllanthus amarus Schum. & Thonn. aqueous extract on paracetamol-induced hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Apichat Muso

    2006-05-01

    Full Text Available The hepatoprotective potential of Phyllanthus amarus Schum. & Thonn. was studied on paracetamolinduced hepatotoxicity in rats by measuring the levels of serum transaminase (SGOT and SGPT, alkaline phosphatase (ALP and bilirubin, as well as by histopathological examination of the liver. Furthermore, the hepatoprotective mechanisms were investigated by determining the amount of paracetamol and its metabolites (glucuronide, sulfate, cysteine and mercapturic acid conjugates in urine and pentobarbital-induced sleeping time to indicate the inhibition on cytochrome P450. The involvement of glutathione was evaluated by determining hepatic reduced glutathione. Its radical scavenging activity, iron chelating activity and total phenolic content were also determined. P. amarus aqueous extracts (0.8, 1.6 or 3.2 g/kg were orally administered twice daily for 7 days prior, for 2 days after, or for 7 days prior and followed by 2 days after a single oral dose of paracetamol (3 g/kg. The results showed that the extract at the doses of 1.6 and 3.2 g/kg decreased the paracetamol-induced hepatotoxicity as indicated by the decrease in SGOT, SGPT, bilirubin and histopathological score while the ALP did not change. Moreover, it is suggested that the hepatoprotective mechanism of this plant was related neither to the inhibition on cytochrome P450, nor to the induction on sulfate and/or glucuronide conjugation pathways of paracetamol, but partly due to the protective effect on the depletion of hepatic reduced glutathione and also its antioxidant activity, especially the radical scavenging and iron chelating activity, which might be related to the high polyphenolic contents. These results support the value of P. amarus, which has been used in Thai folk medicine for the treatment of liver diseases.

  19. Semiprotective Effects of Hempseed Oil on Carbon Tetrachloride-induced Hepatotoxicity in Male Rats: An Ultra-short Toxicological Intervention

    Directory of Open Access Journals (Sweden)

    Mona Hashemzadeh

    2017-12-01

    Full Text Available This study was designed to investigate the protective activity of hempseed oil on carbon tetrachloride (CCl4 hepatotoxicity in male rats at Islamic Azad University, Saveh Branch, Saveh, Iran in 2015. Normal control (NC group was injected intraperitoneally (i.p. with distilled water (0.5 ml/kg; CCl4-intoxicated group (TCC injected CCl4; hempseed oil treated group (HSO gavaged hempseed oil; TCC-HSO group was injected CCl4 prior to intake of hempseed oil and HSO-TCC group was gavaged hempseed oil prior to being injected with CCl4. In all treated groups, toxicity was induced by i.p. injection of CCl4 (0.5 ml/kg for two consecutive days and hemp seed, oil was gavaged at 8 ml/kg in respective group once daily for one week. Plasma alanine aminotransferase (ALT and aspartate transaminase (AST levels increased in TCC. Protection against toxicity in HSO-TCC and TCC-HSO reduced AST and ALT activities compared to TCC. Plasma alkaline phosphatase activity in TCC-HSO and HSO-TCC increased as compared with other groups. CCl4 decreased plasma high-density lipoprotein cholesterol (HDL-C in TCC. Hempseed oil decreased total cholesterol (TC, low-density lipoprotein cholesterol (LDL-C, very low-density lipoprotein cholesterol, and triacylglycerols in HSO compared to NC. Hempseed oil in TCC-HSO and HSO-TCC restored TC, HDL-C, and LDL-C levels to those of NC. Atherogenic index was lower in HSO in comparison to TCC. Based on histopathology, hempseed oil improved CCl4-induced-cardio- and hepatotoxicity in TCC-HSO and HSO-TCC; however, hempseed oil did not prevent CCl4-induced nephrotoxicity. To sum up, hempseed oil has mild protective effects against CCl4 toxicity in male rats.

  20. EFFICIENCY OF BORAGE SEEDS OIL AGAINST GAMMA IRRADIATION-INDUCED HEPATOTOXICITY IN MALE RATS: POSSIBLE ANTIOXIDANT ACTIVITY.

    Science.gov (United States)

    Khattab, Hala A H; Abdallah, Inas Z A; Yousef, Fatimah M; Huwait, Etimad A

    2017-01-01

    Borage ( Borago officinal L.) is an annual herbaceous plant of great interest because its oil contains a high percentage of γ-linolenic acid (GLA). The present work was carried out to detect fatty acids composition of the oil extracted from borage seeds (BO) and its potential effectiveness against γ-irradiation- induced hepatotoxicity in male rats. GC-MS analysis of fatty acids methyl esters of BO was performed to identify fatty acids composition. Sixty rats were divided into five groups (12 rats each): Control, irradiated; rats were exposed to (6.5 Gy) of whole body γ-radiation, BO (50 mg/kg b.wt), irradiated BO post-treated and irradiated BO prepost-treated. Six rats from each group were sacrificed at two time intervals 7 and 15 days post-irradiation. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT) levels, lipids profile, as well as serum and hepatic reduced glutathione (GSH) and lipid peroxide (malondialdehyde) (MDA) levels were assessed. Histopathological examination of liver sections were also carried out. The results showed that the high contents of BO extracted by cold pressing, were linoleic acid (34.23%) and GLA (24.79%). Also, oral administration of BO significantly improved serum levels of liver enzymes, lipids profile, as well as serum and hepatic GSH and MDA levels (p<0.001) as compared with irradiated rats after 15 days post irradiation. Moreover, it exerted marked amelioration against irradiation-induced histopathological changes in liver tissues. The improvement was more pronounced in irradiated BO prepost-treated group than irradiated BO post-treated. BO has a beneficial role in reducing hepatotoxicity and oxidative stress induced by radiation exposure. Therefore, BO may be used as a beneficial supplement for patients during radiotherapy treatment.

  1. Protective Effect of Hericium erinaceus on Alcohol Induced Hepatotoxicity in Mice.

    Science.gov (United States)

    Hao, Lijun; Xie, Yuxi; Wu, Guikai; Cheng, Aibin; Liu, Xiaogang; Zheng, Rongjuan; Huo, Hong; Zhang, Junwei

    2015-01-01

    We investigated the effects of Hericium erinaceus (HEM) on liver injury induced by acute alcohol administration in mice. Mice received ethanol (5 g/kg BW) by gavage every 12 hrs for a total of 3 doses. HEM (200 mg/kg BW) was gavage before ethanol administration. Subsequent serum alanine aminotransferase (ALT) level, aspartate aminotransaminase (AST) level, Maleic dialdehyde (MDA) level, hepatic total antioxidant status (TAOS), and activated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were determined by ELISA and immunohistochemistry, respectively. HEM administration markedly (P < 0.05) decreased serum ALT, AST, and MDA levels. The hepatic histopathological observations showed that HEM had a relatively significant role in mice model, which had alcoholic liver damage. In conclusion, we observed that HEM (200 mg/kg BW) supplementation could restrain the hepatic damage caused by acute alcohol exposure.

  2. Protective Effect of Hericium erinaceus on Alcohol Induced Hepatotoxicity in Mice

    Directory of Open Access Journals (Sweden)

    Lijun Hao

    2015-01-01

    Full Text Available We investigated the effects of Hericium erinaceus (HEM on liver injury induced by acute alcohol administration in mice. Mice received ethanol (5 g/kg BW by gavage every 12 hrs for a total of 3 doses. HEM (200 mg/kg BW was gavage before ethanol administration. Subsequent serum alanine aminotransferase (ALT level, aspartate aminotransaminase (AST level, Maleic dialdehyde (MDA level, hepatic total antioxidant status (TAOS, and activated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB were determined by ELISA and immunohistochemistry, respectively. HEM administration markedly (P<0.05 decreased serum ALT, AST, and MDA levels. The hepatic histopathological observations showed that HEM had a relatively significant role in mice model, which had alcoholic liver damage. In conclusion, we observed that HEM (200 mg/kg BW supplementation could restrain the hepatic damage caused by acute alcohol exposure.

  3. Protective Effect of Hericium erinaceus on Alcohol Induced Hepatotoxicity in Mice

    OpenAIRE

    Hao, Lijun; Xie, Yuxi; Wu, Guikai; Cheng, Aibin; Liu, Xiaogang; Zheng, Rongjuan; Huo, Hong; Zhang, Junwei

    2015-01-01

    We investigated the effects of Hericium erinaceus (HEM) on liver injury induced by acute alcohol administration in mice. Mice received ethanol (5?g/kg?BW) by gavage every 12?hrs for a total of 3 doses. HEM (200?mg/kg?BW) was gavage before ethanol administration. Subsequent serum alanine aminotransferase (ALT) level, aspartate aminotransaminase (AST) level, Maleic dialdehyde (MDA) level, hepatic total antioxidant status (TAOS), and activated nuclear factor kappa-light-chain-enhancer of activat...

  4. Acute Pancreatitis

    DEFF Research Database (Denmark)

    Bertilsson, Sara; Håkansson, Anders; Kalaitzakis, Evangelos

    2017-01-01

    Aims: We aimed to evaluate the potential relation between the incidence of (alcoholic and non-alcoholic) acute pancreatitis (AP) and alcohol consumption in the general population, and whether the occurrence of AP shows any seasonal variation, particularly in relation to periods with expected...... consumption in the general population do not appear to be related to changes in the incidence of AP and there are no significant seasonal differences in the occurrence of AP in Sweden. Short summary: The incidence of acute pancreatitis (AP) is increasing, and alcohol is still recognized as one of the most...

  5. Adderall Induced Acute Liver Injury: A Rare Case and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Rohini R. Vanga

    2013-01-01

    Full Text Available Adderall (dextroamphetamine/amphetamine is a widely prescribed medicine for the treatment of attention-deficit/hyperactivity disorder (ADHD and is considered safe with due precautions. Use of prescribed Adderall without intention to overdose as a cause of acute liver injury is extremely rare, and to our knowledge no cases have been reported in the English literature. Amphetamine is an ingredient of recreational drugs such as Ecstacy and is known to cause hepatotoxicity. We describe here the case of a 55-year-old woman who developed acute liver failure during the treatment of ADHD with Adderall. She presented to the emergency room with worsening abdominal pain, malaise, and jaundice requiring hospitalization. She had a past history of partial hepatic resection secondary to metastasis from colon cancer which was under remission at the time of presentation. She recovered after intensive monitoring and conservative management. Adderall should be used carefully in individuals with underlying liver conditions.

  6. Acute liver injury associated with a newer formulation of the herbal weight loss supplement Hydroxycut.

    Science.gov (United States)

    Araujo, James L; Worman, Howard J

    2015-05-06

    Despite the widespread use of herbal and dietary supplements (HDS), serious cases of hepatotoxicity have been reported. The popular herbal weight loss supplement, Hydroxycut, has previously been implicated in acute liver injury. Since its introduction, Hydroxycut has undergone successive transformations in its formulation; yet, cases of liver injury have remained an ongoing problem. We report a case of a 41-year-old Hispanic man who developed acute hepatocellular liver injury with associated nausea, vomiting, jaundice, fatigue and asterixis attributed to the use of a newer formulation of Hydroxycut, SX-7 Clean Sensory. The patient required hospitalisation and improved with supportive therapy. Despite successive transformations in its formulation, potential liver injury appears to remain an ongoing problem with Hydroxycut. Our case illustrates the importance of obtaining a thorough medication history, including HDS, regardless of new or reformulated product marketing efforts. 2015 BMJ Publishing Group Ltd.

  7. Increased plasma levels of microparticles expressing CD39 and CD133 in acute liver injury

    DEFF Research Database (Denmark)

    Schmelzle, Moritz; Splith, Katrin; Wiuff Andersen, Lars

    2013-01-01

    BACKGROUND: We have previously demonstrated that CD133 and CD39 are expressed by hematopoietic stem cells (HSC), which are mobilized after liver injury and target sites of injury, limit vascular inflammation, and boost hepatic regeneration. Plasma microparticles (MP) expressing CD39 can block...... sacrificed and plasma MP were isolated by ultracentrifugation. HSC and CD133 MP levels were analyzed by fluorescence-activated cell sorting. Patients were enrolled with acute (n=5) and acute on chronic (n=5) liver injury with matched controls (n=7). Blood was collected at admission and plasma CD133 and CD39...... MP subsets were analyzed by fluorescence-activated cell sorting. RESULTS: HSC and CD133 MP levels were significantly increased only in the plasma of wild-type mice with acetaminophen hepatotoxicity (P

  8. Genetically obese (ob/ob) mice are resistant to the lethal effects of thioacetamide hepatotoxicity

    International Nuclear Information System (INIS)

    Won, Young-Suk; Song, Ji-Won; Lim, Jong-Hwan; Lee, Mee-Young; Moon, Og-Sung; Kim, Hyoung-Chin; Son, Hwa-Young; Kwon, Hyo-Jung

    2016-01-01

    Obesity increases the risk of chronic liver diseases, including viral hepatitis, alcohol-induced liver disease, and non-alcoholic steatohepatitis. In this study, we investigated the effects of obesity in acute hepatic failure using a murine model of thioacetamide (TA)-induced liver injury. Genetically obese ob/ob mice, together with non-obese ob/+ littermates, were subjected to a single intraperitoneal injection of TA, and examined for signs of hepatic injury. ob/ob mice showed a significantly higher survival rate, lower levels of serum alanine aminotransferase and aspartate aminotransferase, and less hepatic necrosis and apoptosis, compared with ob/+ mice. In addition, ob/ob mice exhibited significantly lower levels of malondialdehyde and significantly higher levels of glutathione and antioxidant enzyme activities compared with their ob/+ counterparts. Bioactivation analyses revealed reduced plasma clearance of TA and covalent binding of [ 14 C]TA to liver macromolecules in ob/ob mice. Together, these data demonstrate that genetically obese mice are resistant to TA-induced acute liver injury through diminished bioactivation of TA and antioxidant effects. - Highlights: • ob/ob mice are resistant to lethal doses of thioacetamide, compared to ob/+ mice. • ob/ob mice show reduced oxidative stress and enhanced antioxidant enzyme activity. • ob/ob mice exhibit diminished bioactivation of thioacetamide.

  9. Genetically obese (ob/ob) mice are resistant to the lethal effects of thioacetamide hepatotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Won, Young-Suk [Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk (Korea, Republic of); Song, Ji-Won [Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon (Korea, Republic of); Lim, Jong-Hwan [Huons Research Center, Gyonggido (Korea, Republic of); Lee, Mee-Young [Herbal Medicine Formulation Research Group, Korea Institute of Oriental Medicine, Daejeon (Korea, Republic of); Moon, Og-Sung; Kim, Hyoung-Chin [Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk (Korea, Republic of); Son, Hwa-Young [Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon (Korea, Republic of); Kwon, Hyo-Jung, E-mail: hyojung@cnu.ac.kr [Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon (Korea, Republic of)

    2016-01-15

    Obesity increases the risk of chronic liver diseases, including viral hepatitis, alcohol-induced liver disease, and non-alcoholic steatohepatitis. In this study, we investigated the effects of obesity in acute hepatic failure using a murine model of thioacetamide (TA)-induced liver injury. Genetically obese ob/ob mice, together with non-obese ob/+ littermates, were subjected to a single intraperitoneal injection of TA, and examined for signs of hepatic injury. ob/ob mice showed a significantly higher survival rate, lower levels of serum alanine aminotransferase and aspartate aminotransferase, and less hepatic necrosis and apoptosis, compared with ob/+ mice. In addition, ob/ob mice exhibited significantly lower levels of malondialdehyde and significantly higher levels of glutathione and antioxidant enzyme activities compared with their ob/+ counterparts. Bioactivation analyses revealed reduced plasma clearance of TA and covalent binding of [{sup 14}C]TA to liver macromolecules in ob/ob mice. Together, these data demonstrate that genetically obese mice are resistant to TA-induced acute liver injury through diminished bioactivation of TA and antioxidant effects. - Highlights: • ob/ob mice are resistant to lethal doses of thioacetamide, compared to ob/+ mice. • ob/ob mice show reduced oxidative stress and enhanced antioxidant enzyme activity. • ob/ob mice exhibit diminished bioactivation of thioacetamide.

  10. Current Understanding of Acute Bovine Liver Disease in Australia

    Directory of Open Access Journals (Sweden)

    Elizabeth Read

    2016-12-01

    Full Text Available Acute bovine liver disease (ABLD is a hepatotoxicity principally of cattle which occurs in southern regions of Australia. Severely affected animals undergo rapid clinical progression with mortalities often occurring prior to the recognition of clinical signs. Less severely affected animals develop photosensitization and a proportion can develop liver failure. The characteristic histopathological lesion in acute fatal cases is severe, with acute necrosis of periportal hepatocytes with hemorrhage into the necrotic areas. Currently there are a small number of toxins that are known to cause periportal necrosis in cattle, although none of these have so far been linked to ABLD. Furthermore, ABLD has frequently been associated with the presence of rough dog’s tail grass (Cynosurus echinatus and Drechslera spp. fungi in the pasture system, but it is currently unknown if these are etiological factors. Much of the knowledge about ABLD is contained within case reports, with very little experimental research investigating the specific cause(s. This review provides an overview of the current and most recently published knowledge of ABLD. It also draws on wider research and unpublished reports to suggest possible fungi and mycotoxins that may give rise to ABLD.

  11. Investigations on the nephrotoxicity and hepatotoxicity of trivalent and hexavalent chromium compounds.

    Science.gov (United States)

    Dartsch, P C; Hildenbrand, S; Kimmel, R; Schmahl, F W

    1998-09-01

    In contrast to trivalent chromium (Cr(III)) compounds, hexavalent chromium ((Cr(VI)) compounds are oxidizing agents capable of directly inducing tissue damage and possessing carcinogenic, mutagenic and teratogenic potency. After oral or dermal absorption of Cr(VI), the kidney is the main target organ for chromium accumulation, which might result in acute tubular necrosis in humans. In contrast, an acute toxic effect of Cr(VI) on the liver has not yet been described. Therefore, we used two established epithelial cell lines from the kidney (Opossum kidney cells) and the liver (Hep G2 cells) to design an in vitro-assay which is able to examine acute toxic effects of chromium compounds. Cells of both cell lines were treated with various concentrations of Cr(III) and Cr(VI) ranging from 0.01 micromol/l to 1 mmol/l for 24 h. Thereafter, cell morphology, organization of the intracellular cytoskeleton, number of viable cells and mean cell volume were examined. The results show that Cr(VI), but not Cr(III), has an acute cytotoxic effect and causes a dose-dependent loss in cell viability. The effective dose that caused 50% of cell death was 5 micromol/l for kidney epithelial cells and 50 micromol/l for liver epithelial cells. This means that kidney epithelial cells are 10 times more sensitive towards Cr(VI) treatment than liver epithelial cells and this might explain the known nephrotoxicity in vivo. The loss in cell viability was accompanied by a rounding and detachment of the cells and a marked reduction of intracellular F-actin-containing stress fibers. Microtubules and intermediate-sized filaments were observed to be unaffected. Only in the case of kidney epithelial cells, a dose-dependent cell volume increase was observed after Cr(VI) treatment at concentrations up to 50 micromol/l. At higher concentrations, the cell volume decreased due to the high number of cells undergoing lysis and the appearance of cellular fragments. Various chloride channel blockers with

  12. Lupus-prone NZBWF1/J mice, defective in cytokine signaling, are resistant to fumonisin hepatotoxicity despite accumulation of liver sphinganine

    Energy Technology Data Exchange (ETDEWEB)

    Sharma, Raghubir P [Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7389 (United States); Quanren, He [Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7389 (United States); Riley, Ronald T [Toxicology and Mycotoxin Research Unit, USDA-ARS, Athens, GA 30604 (United States)

    2005-12-01

    Fumonisin B{sub 1} (FB{sub 1}) is a mycotoxin produced by Fusarium verticillioides, commonly present in corn and other cereals. Exposure to FB{sub 1} causes organ-specific diseases in various species, e.g., equine leukoencephalomalacia and porcine pulmonary edema; in mice the response is hepatotoxicity. We earlier reported that ceramide synthase inhibition by FB{sub 1}, the initial biochemical effect of this mycotoxin, results in modulation of cytokine network in response to accumulated free sphingoid bases. In the current study we used NZB/NZW-F1 (NZBW) mice that have modified cytokine expression and develop lupus beginning at 5 months of age. The NZBW and C57BL/6J (CBL) mice (appropriate control) were given five daily subcutaneous injections of either saline or 2.25 mg FB{sub 1}/kg/day and euthanized 24 h after the last treatment. Peripheral leukocyte counts were higher after exposure to FB{sub 1} in CBL but not in NZBW. FB{sub 1} treatment caused increases of plasma alanine aminotransferase and aspartate aminotransferase activity in CBL mice indicating hepatotoxicity; no elevation of circulating liver enzymes was recorded in NZBW mice. Hepatotoxic responses were confirmed by microscopic evaluation of apoptotic cells. The FB{sub 1}-induced proliferation of cells observed in CBL strain was abolished in NZBW animals. The sphinganine accumulation in liver after FB{sub 1} was equal in both strains of mice. The NZBW strain lacked the FB{sub 1}-induced increases in the expression of liver tumor necrosis factor {alpha}, interferon {gamma}, receptor interacting protein (RIP), and tumor necrosis factor {alpha}-related apoptosis-inducing ligand (TRAIL), observed in CBL. Results confirmed our hypothesis that initial altered sphingolipid metabolism caused by FB{sub 1} leads to perturbation of liver cytokine network and ultimate cellular injury; the mice deficient in cytokine signaling are refractory to FB{sub 1} hepatotoxicity.

  13. Lupus-prone NZBWF1/J mice, defective in cytokine signaling, are resistant to fumonisin hepatotoxicity despite accumulation of liver sphinganine

    International Nuclear Information System (INIS)

    Sharma, Raghubir P.; He Quanren; Riley, Ronald T.

    2005-01-01

    Fumonisin B 1 (FB 1 ) is a mycotoxin produced by Fusarium verticillioides, commonly present in corn and other cereals. Exposure to FB 1 causes organ-specific diseases in various species, e.g., equine leukoencephalomalacia and porcine pulmonary edema; in mice the response is hepatotoxicity. We earlier reported that ceramide synthase inhibition by FB 1 , the initial biochemical effect of this mycotoxin, results in modulation of cytokine network in response to accumulated free sphingoid bases. In the current study we used NZB/NZW-F1 (NZBW) mice that have modified cytokine expression and develop lupus beginning at 5 months of age. The NZBW and C57BL/6J (CBL) mice (appropriate control) were given five daily subcutaneous injections of either saline or 2.25 mg FB 1 /kg/day and euthanized 24 h after the last treatment. Peripheral leukocyte counts were higher after exposure to FB 1 in CBL but not in NZBW. FB 1 treatment caused increases of plasma alanine aminotransferase and aspartate aminotransferase activity in CBL mice indicating hepatotoxicity; no elevation of circulating liver enzymes was recorded in NZBW mice. Hepatotoxic responses were confirmed by microscopic evaluation of apoptotic cells. The FB 1 -induced proliferation of cells observed in CBL strain was abolished in NZBW animals. The sphinganine accumulation in liver after FB 1 was equal in both strains of mice. The NZBW strain lacked the FB 1 -induced increases in the expression of liver tumor necrosis factor α, interferon γ, receptor interacting protein (RIP), and tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL), observed in CBL. Results confirmed our hypothesis that initial altered sphingolipid metabolism caused by FB 1 leads to perturbation of liver cytokine network and ultimate cellular injury; the mice deficient in cytokine signaling are refractory to FB 1 hepatotoxicity

  14. Strategy for Hepatotoxicity Prediction Induced by Drug Reactive Metabolites Using Human Liver Microsome and Online 2D-Nano-LC-MS Analysis.

    Science.gov (United States)

    Zhuo, Yue; Wu, Jian-Lin; Yan, Xiaojing; Guo, Ming-Quan; Liu, Ning; Zhou, Hua; Liu, Liang; Li, Na

    2017-12-19

    Hepatotoxicity is a leading cause of drug withdrawal from the market; thus, the assessment of potential drug induced liver injury (DILI) in preclinical trials is necessary. More and more research has shown that the covalent modification of drug reactive metabolites (RMs) for cellular proteins is a possible reason for DILI. Unfortunately, so far no appropriate method can be employed to evaluate this kind of DILI due to the low abundance of RM-protein adducts in complex biological samples. In this study, we proposed a mechanism-based strategy to solve this problem using human liver microsomes (HLMs) and online 2D nano-LC-MS analysis. First, RM modification patterns and potential modified AA residues are determined using HLM and model amino acids (AAs) by UHPLC-Q-TOF-MS. Then, a new online 2D-nano-LC-Q-TOF-MS method is established and applied to separate the digested modified microsomal peptides from high abundance peptides followed by identification of RM-modified proteins using Mascot, in which RM modification patterns on specific AA residues are added. Finally, the functions and relationship with hepatotoxicity of the RM-modified proteins are investigated using ingenuity pathway analysis (IPA) to predict the possible DILI. Using this strategy, 21 proteins were found to be modified by RMs of toosendanin, a hepatotoxic drug with complex structure, and some of them have been reported to be associated with hepatotoxicity. This strategy emphasizes the identification of drug RM-modified proteins in complex biological samples, and no pretreatment is required for the drugs. Consequently, it may serve as a valuable method to predict potential DILI, especially for complex compounds.

  15. Camellia sinensis L. Extract and Its Potential Beneficial Effects in Antioxidant, Anti-Inflammatory, Anti-Hepatotoxic, and Anti-Tyrosinase Activities

    Directory of Open Access Journals (Sweden)

    Surached Thitimuta

    2017-03-01

    Full Text Available The aims of this study were to investigate the potential benefits of antioxidant, anti-inflammatory, anti-hepatotoxic, and anti-tyrosinase activities of a methanolic extract of fresh tea leaves (FTE (Camellia sinensis L.. The antioxidant capacity was investigated using three different methods at different temperatures. The anti-inflammatory activity was studied in vitro by the inhibition of 5-lipoxygenase assay. The anti-hepatotoxic effect was investigated in CCl4-induced liver injury in rats. The anti-tyrosinase activities of the FTE and its principal phenolic compounds were investigated in l-3,4-dihydroxyphenylalanine (l-DOPA oxidation by a mushroom tyrosinase. A molecular docking study was conducted to determine how the FTE’s principal catechins interact with the tyrosinase. The FTE exhibited the best shelf life at low temperatures and demonstrated concentration-dependent antioxidant, anti-inflammatory, anti-hepatotoxic, and anti-tyrosinase effects compared to positive references. Treatment of rats with the FTE at 2000 mg/kg/day for 28 consecutive days reversed CCl4-induced oxidative damage in hepatic tissues by lowering the levels of alanine aminotransferase by 69% and malondialdehyde by 90%. Our findings suggest that the FTE has the capacity to scavenge free radicals and can protect against oxidative stress induced by CCl4 intoxication. The docking results were consistent with our in vitro data, indicating the anti-tyrosinase potency of the principal catechins.

  16. Camellia sinensis L. Extract and Its Potential Beneficial Effects in Antioxidant, Anti-Inflammatory, Anti-Hepatotoxic, and Anti-Tyrosinase Activities.

    Science.gov (United States)

    Thitimuta, Surached; Pithayanukul, Pimolpan; Nithitanakool, Saruth; Bavovada, Rapepol; Leanpolchareanchai, Jiraporn; Saparpakorn, Patchreenart

    2017-03-04

    The aims of this study were to investigate the potential benefits of antioxidant, anti-inflammatory, anti-hepatotoxic, and anti-tyrosinase activities of a methanolic extract of fresh tea leaves (FTE) ( Camellia sinensis L.). The antioxidant capacity was investigated using three different methods at different temperatures. The anti-inflammatory activity was studied in vitro by the inhibition of 5-lipoxygenase assay. The anti-hepatotoxic effect was investigated in CCl₄-induced liver injury in rats. The anti-tyrosinase activities of the FTE and its principal phenolic compounds were investigated in l-3,4-dihydroxyphenylalanine (l-DOPA) oxidation by a mushroom tyrosinase. A molecular docking study was conducted to determine how the FTE's principal catechins interact with the tyrosinase. The FTE exhibited the best shelf life at low temperatures and demonstrated concentration-dependent antioxidant, anti-inflammatory, anti-hepatotoxic, and anti-tyrosinase effects compared to positive references. Treatment of rats with the FTE at 2000 mg/kg/day for 28 consecutive days reversed CCl₄-induced oxidative damage in hepatic tissues by lowering the levels of alanine aminotransferase by 69% and malondialdehyde by 90%. Our findings suggest that the FTE has the capacity to scavenge free radicals and can protect against oxidative stress induced by CCl₄ intoxication. The docking results were consistent with our in vitro data, indicating the anti-tyrosinase potency of the principal catechins.

  17. Effects of N-acetyl cysteine on oxidative stress and TNF-α gene expression in diclofenac-induced hepatotoxicity in rats.

    Science.gov (United States)

    Nouri, Ali; Heidarian, Esfandiar; Nikoukar, Morteza

    2017-10-01

    The consumption of non-steroidal anti-inflammatory drug, such as diclofenac, can lead to hepatotoxicity. In the present study, protective effect of N-acetyl cysteine (NAC) on diclofenac-induced hepatotoxicity was investigated. Thirty-two male rats were divided into four groups. Group 1 (control group) was treated with normal saline (1 ml/kg, i.p.) for 4 d. Group 2 (test without treatment) received diclofenac only (50 mg/kg, i.p.) for 4 d. Groups 3 and 4 received diclofenac (50 mg/kg, i.p.) plus NAC (150 mg/kg, p.o) and silymarin (100 mg/kg, p.o) for 4 d, respectively. At the end of experiment, serum glutamate pyruvate transaminase (GPT), glutamate oxaloacetate transaminase (GOT), alkaline phosphatase (ALP), lipid profile, uric acid, protein carbonyl content, MDA, liver TNF-α, ferric-reducing antioxidant power, liver catalase, superoxide dismutase, vitamin C, and histopathological examination were done. In group 2, diclofenac caused a significant increase (p diclofenac-induced hepatotoxicity in rats due to not only reduces liver inflammatory cells, TNF-α, serum MDA, and PC but also through increases liver vitamin C, catalase, and superoxide dismutase activities.

  18. Acute liver failure in a term neonate after repeated paracetamol administration

    Directory of Open Access Journals (Sweden)

    Fabio Bucaretchi

    2014-03-01

    Full Text Available Objective: Severe hepatotoxicity caused by paracetamol is rare in neonates. We report a case of paracetamol-induced acute liver failure in a term neonate. Case description: A 26-day-old boy was admitted with intestinal bleeding, shock signs, slight liver enlargement, coagulopathy, metabolic acidosis (pH=7.21; bicarbonate: 7.1mEq/L, hypoglycemia (18mg/dL, increased serum aminotransferase activity (AST=4,039IU/L; ALT=1,087IU/L and hyperbilirubinemia (total: 9.57mg/dL; direct: 6.18mg/dL after receiving oral paracetamol (10mg/kg/dose every 4 hours for three consecutive days (total dose around 180mg/kg; serum concentration 36-48 hours after the last dose of 77µg/ mL. Apart from supportive measures, the patient was successfully treated with intravenous N-acetylcysteine infusion during 11 consecutive days, and was discharged on day 34. The follow-up revealed full recovery of clinical and of laboratory findings of hepatic function. Comments: The paracetamol pharmacokinetics and pharmacodynamics in neonates and infants differ substantially from those in older children and adults. Despite the reduced rates of metabolism by the P-450 CYP2E1 enzyme system and the increased ability to synthesize glutathione - which provides greater resistance after overdoses -, it is possible to produce hepatotoxic metabolites (N-acetyl-p-benzoquinone that cause hepatocellular damage, if glutathione sources are depleted. Paracetamol clearance is reduced and the half-life of elimination is prolonged. Therefore, a particular dosing regimen should be followed due to the toxicity risk of cumulative doses. This report highlights the risk for severe hepatotoxicity in neonates after paracetamol multiple doses for more than two to three days.

  19. Co-administration of fresh grape fruit juice (GFJ and bergamottin prevented paracetamol induced hepatotoxicity after paracetamol overdose in rats

    Directory of Open Access Journals (Sweden)

    Refuoe Baleni

    2015-01-01

    Full Text Available The aim of this study was to evaluate small doses of known cytochrome P450 enzyme inhibitors, grapefruit juice (GFJ and one of its components, bergamottin (BGT, for the prevention of paracetamol (PAR-induced hepatotoxicity after overdose in rats. Six groups of 15 Sprague Dawley (SD rats each were treated with single oral doses of either saline, PAR only 1725 mg/kg, PAR + GFJ low dose (2 ml and PAR + GFJ high dose (3 ml, PAR + BGT 0.05 mg/kg (BGT-low and PAR + BGT 0.22 mg/kg (BGT-high. Thereafter, 5 rats from each group were sacrificed after 24, 48 and 72 h and, on each occasion, blood samples were collected for determination of liver and renal function, full blood count (FBC and PAR concentration. A piece of liver was sent for histopathology. By 48 h the liver enzymes in the PAR-only group were significantly (P < 0.05 higher than in the PAR + GFJ and PAR + BGT groups, i.e., alanine transaminase (ALT 837 ± 268 u/L and aspertate transaminase (AST 1359 ± 405 for PAR only; versus ALT 34 ± 48.8 u/L and AST 238 ± 221 for PAR + GFJ-high; ALT 22 ± 13.9 and AST168 ± 49.6 for PAR + BGT-high; and ALT 52 ± 7.2 u/L and AST 147 ± 153 for the control group. The results correlated with the histopathology findings where livers of the PAR-only group exhibited severe centrilobular and hepatocyte necrosis. In conclusion, GFJ and BGT prevented PAR-induced hepatotoxicity after PAR overdose in rats, and this calls for appropriate observation studies in humans.

  20. Acute abdomen

    Directory of Open Access Journals (Sweden)

    Wig J

    1978-01-01

    Full Text Available 550 cases of acute abdomen have been analysed in detail includ-ing their clinical presentation and operative findings. Males are more frequently affected than females in a ratio of 3: 1. More than 45% of patients presented after 48 hours of onset of symptoms. Intestinal obstruction was the commonest cause of acute abdomen (47.6%. External hernia was responsible for 26% of cases of intestinal obstruction. Perforated peptic ulcer was the commonest cause of peritonitis in the present series (31.7% while incidence of biliary peritonitis was only 2.4%.. The clinical accuracy rate was 87%. The mortality in operated cases was high (10% while the over-all mortality rate was 7.5%.

  1. Acute Blindness.

    Science.gov (United States)

    Meekins, Jessica M

    2015-09-01

    Sudden loss of vision is an ophthalmic emergency with numerous possible causes. Abnormalities may occur at any point within the complex vision pathway, from retina to optic nerve to the visual center in the occipital lobe. This article reviews specific prechiasm (retina and optic nerve) and cerebral cortical diseases that lead to acute blindness. Information regarding specific etiologies, pathophysiology, diagnosis, treatment, and prognosis for vision is discussed. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Study of the protective effect of hydroalcoholic extract microemulsion of Teucrium polium .L against bromobenzene -induced hepatotoxicity in mice

    Directory of Open Access Journals (Sweden)

    alihasan Rahmani

    2015-01-01

    Full Text Available Background : Liver is a major organ of the body, which can be exposed to various chemicals, drugs and many other xenobiotics such as bromobenzene. The aim of this study was to find out the protective effect of hydroalcoholic extract microemulsion of Teucrium polium against hepatotoxicity induced by bromobenzene. Materials and Methods: Animals were divided into eight groups, with ten animals in each group. Group 1-3 received respectively normal saline base of microemulsion and extract microemulsions in dose of 400 mg/kg orally for 10 days. Group 4 received bromobenzene (0.36 ml/kg, ip only on the 10th day groups 5-8 received extract microemulsions orally in doses of 50, 100, 200 and 400 mg/kg respectively, during 10 days and bromobenzene (0.36 ml/kg, ip on the 10th day 1 hour after last dose of extract. 24 hours later, the animals were bled and enzymes ALT, AST and ALP were measured. Animal liver was removed for histological studies. Results: The results showed a significant increase in liver enzyme activity by bromobenzene. The treated groups with Teucrium polium showed a significant decrease in liver enzyme activity in doses of 100, 200 and 400 mg/kg (P<0.05. Histological observations also confirmed the results. Conclusion: The results revealed that hydroalcoholic extract microemulsion of Teucrium polium has protective effect on liver toxicity induced by bromobenzene

  3. Exacerbation of N-nitrosodiethylamine Induced Hepatotoxicity and DNA Damage in Mice Exposed to Chronic Unpredictable Stress

    Directory of Open Access Journals (Sweden)

    Nayeem Bilal

    2017-06-01

    Full Text Available Psychological stress contributes to increased susceptibility to a number of diseases including cancer. The present study was designed to assess the effect of chronic unpredictable stress on N-nitrosodiethylamine induced liver toxicity in terms of in vivo antioxidant status and DNA damage in Swiss albino mice. The animals used in this study were randomized into different groups based on the treatment with N-nitrosodiethylamine or chronic unpredictable stress alone and post-stress administration of N-nitrosodiethylamine. The mice were sacrificed after 12 weeks of treatment, and the status of major enzymatic and non-enzymatic antioxidants, liver function markers, lipid peroxidation and the extent of DNA damage were determined in circulation and liver tissues of all the groups. The N-nitrosodiethylamine treated group showed significantly compromised levels of the antioxidant enzymes, lipid peroxidation, and the liver function markers with enhanced DNA damage as compared to chronic unpredictable stress or control groups. A similar but less typical pattern observed in the chronic unpredictable stress treated mice. All the measured biochemical parameters were significantly altered in the group treated with the combination of chronic unpredictable stress and N-nitrosodiethylamine when compared to controls, or chronic unpredictable stress alone and/or N-nitrosodiethylamine alone treated groups. Thus, exposure to continuous, unpredictable stress conditions even in general life may significantly enhance the hepatotoxic potential of N-nitrosodiethylamine through an increase in the oxidative stress and DNA damage.

  4. Aqueous and ethanolic leaf extracts of Ocimum basilicum (sweet basil) protect against sodium arsenite-induced hepatotoxicity in Wistar rats.

    Science.gov (United States)

    Gbadegesin, M A; Odunola, O A

    2010-11-25

    We evaluated the effects of aqueous and ethanolic leaf extracts of Ocimum basilicum (sweet basil) on sodium arsenite-induced hepatotoxicity in Wistar rats. We observed that treatment of the animals with the extracts before or just after sodium arsenite administration significantly (p < 0.05) reduced mean liver and serum γ-Glutamyl transferase (γGT), and serum alkaline phosphatase (ALP) activities when compared with the group administered the toxin alone. In addition, treatments of the animals with aqueous or ethanolic extract of O. basilicum before the administration of sodium arsenite resulted in the attenuation of the sodium arsenite-induced aspartate and alanine aminotransferase activities: ALT (from 282.6% to 167.7% and 157.8%), AST (from 325.1% to 173.5% and 164.2%) for the group administered sodium arsenite alone, the aqueous extracts plus sodium arsenite, and ethanolic extracts plus sodium arsenite respectively, expressed as percentage of the negative control. These findings support the presence of hepatoprotective activity in the O.basilicum extracts.

  5. Herbal does not mean innocuous: ten cases of severe hepatotoxicity associated with dietary supplements from Herbalife products.

    Science.gov (United States)

    Schoepfer, Alain M; Engel, Antoinette; Fattinger, Karin; Marbet, Urs A; Criblez, Dominique; Reichen, Juerg; Zimmermann, Arthur; Oneta, Carl M

    2007-10-01

    Herbal agents are popular and perceived as safe because they are supposedly 'natural'. We report 10 cases of toxic hepatitis implicating Herbalife products. To determine the prevalence and outcome of hepatotoxicity due to Herbalife products. A questionnaire was sent to all public Swiss hospitals. Reported cases were subjected to causality assessment using the CIOMS criteria. Twelve cases of toxic hepatitis implicating Herbalife preparations (1998-2004) were retrieved, 10 sufficiently documented to permit causality analysis. Median age of patients was 51 years (range 30-69) and latency to onset was 5 months (0.5-144). Liver biopsy (7/10) showed hepatic necrosis, marked lymphocytic/eosinophilic infiltration and cholestasis in five patients. One patient with fulminant liver failure was successfully transplanted; the explant showed giant cell hepatitis. Sinusoidal obstruction syndrome was observed in one case. Three patients without liver biopsy presented with hepatocellular (2) or mixed (1) liver injury. Causality assessment of adverse drug reaction was classified as certain in two, probable in seven and possible in one case(s), respectively. We present a case series of toxic hepatitis implicating Herbalife products. Liver toxicity may be severe. A more detailed declaration of components and pro-active role of regulatory agencies would be desirable.

  6. An effective assessment of valproate sodium-induced hepatotoxicity with UPLC-MS and (1)HNMR-based metabonomics approach.

    Science.gov (United States)

    Huo, Taoguang; Chen, Xi; Lu, Xiumei; Qu, Lianyue; Liu, Yang; Cai, Shuang

    2014-10-15

    Valproate sodium is one of the most prescribed antiepileptic drugs. However, valproate sodium has various side effects, especially its toxicity on liver. Current markers for toxicity reflect mostly the late stages of tissue damage; thus, more efficient methods for toxicity evaluation are desired. To evaluate the toxicity of valproate sodium on liver, we performed both UPLC-MS and (1)HNMR-based metabonomics analysis of serum samples from 34 epileptic patients (age: 42.0±18.6, 18 male/16 female) after valproate sodium treatment. Compared to conventional markers, the serum metabolic profiles provided clear distinction of the valproate sodium induced normal liver function and abnormal liver function in epileptic patients. Through multivariate statistical analysis, we identified marker metabolites associated with the hepatotoxicity induced by valproate sodium, such as glucose, lactate, acetoacetate, VLDL/LDL, lysophosphatidylcholines, phosphatidylcholines, choline, creatine, amino acids, N-acetyl glycoprotein, pyruvate and uric acid. This metabonomics approach may provide effective way to evaluate the valproate sodium-induced toxicity in a manner that can complement current measures. This approach is expected to find broader application in other drug-induced toxicity assessment. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Protective effect of ethyl acetate fraction of Rhododendron arboreum flowers against carbon tetrachloride-induced hepatotoxicity in experimental models.

    Science.gov (United States)

    Verma, Neeraj; Singh, Anil P; Amresh, G; Sahu, P K; Rao, Ch V

    2011-05-01

    To evaluate the hepatoprotective potential of ethyl acetate fraction of Rhododendron arboreum (Family: Ericaceae) in Wistar rats against carbon tetrachloride (CCl(4))-induced liver damage in preventive and curative models. Fraction at a dose of 100, 200, and 400 mg/kg was administered orally once daily for 14 days in CCl(4)-treated groups (II, III, IV, V and VI). The serum levels of glutamic oxaloacetic transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase (SALP), γ-glutamyltransferase (γ -GT), and bilirubin were estimated along with activities of glutathione S-transferase (GST), glutathione reductase, hepatic malondialdehyde formation, and glutathione content. The substantially elevated serum enzymatic activities of SGOT, SGPT, SALP, γ-GT, and bilirubin due to CCl(4) treatment were restored toward normal in a dose-dependent manner. Meanwhile, the decreased activities of GST and glutathione reductase were also restored toward normal. In addition, ethyl acetate fraction also significantly prevented the elevation of hepatic malondialdehyde formation and depletion of reduced glutathione content in the liver of CCl(4)-intoxicated rats in a dose-dependent manner. Silymarin used as standard reference also exhibited significant hepatoprotective activity on post-treatment against CCl(4)-induced hepatotoxicity in rats. The biochemical observations were supplemented with histopathological examination of rat liver sections. The results of this study strongly indicate that ethyl acetate fraction has a potent hepatoprotective action against CCl(4)-induced hepatic damage in rats.

  8. Autophagy Protects against CYP2E1/Chronic Ethanol-Induced Hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Yongke Lu

    2015-10-01

    Full Text Available Autophagy is an intracellular pathway by which lysosomes degrade and recycle long-lived proteins and cellular organelles. The effects of ethanol on autophagy are complex but recent studies have shown that autophagy serves a protective function against ethanol-induced liver injury. Autophagy was found to also be protective against CYP2E1-dependent toxicity in vitro in HepG2 cells which express CYP2E1 and in vivo in an acute alcohol/CYPE1-dependent liver injury model. The goal of the current report was to extend the previous in vitro and acute in vivo experiments to a chronic ethanol model to evaluate whether autophagy is also protective against CYP2E1-dependent liver injury in a chronic ethanol-fed mouse model. Wild type (WT, CYP2E1 knockout (KO or CYP2E1 humanized transgenic knockin (KI, mice were fed an ethanol liquid diet or control dextrose diet for four weeks. In the last week, some mice received either saline or 3-methyladenine (3-MA, an inhibitor of autophagy, or rapamycin, which stimulates autophagy. Inhibition of autophagy by 3-MA potentiated the ethanol-induced increases in serum transaminase and triglyceride levels in the WT and KI mice but not KO mice, while rapamycin prevented the ethanol liver injury. Treatment with 3-MA enhanced the ethanol-induced fat accumulation in WT mice and caused necrosis in the KI mice; little or no effect was found in the ethanol-fed KO mice or any of the dextrose-fed mice. 3-MA treatment further lowered the ethanol-decrease in hepatic GSH levels and further increased formation of TBARS in WT and KI mice, whereas rapamycin blunted these effects of ethanol. Neither 3-MA nor rapamycin treatment affected CYP2E1 catalytic activity or content or the induction CYP2E1 by ethanol. The 3-MA treatment decreased levels of Beclin-1 and Atg 7 but increased levels of p62 in the ethanol-fed WT and KI mice whereas rapamycin had the opposite effects, validating inhibition and stimulation of autophagy, respectively. These

  9. Hepato- and neuro-protective influences of biopropolis on thioacetamide-induced acute hepatic encephalopathy in rats.

    Science.gov (United States)

    Mostafa, Rasha E; Salama, Abeer A A; Abdel-Rahman, Rehab F; Ogaly, Hanan A

    2017-05-01

    Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that ultimately occurs as a complication of acute or chronic liver failure; accompanied by hyperammonemia. This study aimed to evaluate the potential of biopropolis as a hepato- and neuro-protective agent using thioacetamide (TAA)-induced acute HE in rats as a model. Sixty Wistar rats were divided into 5 groups: Group 1 (normal control) received only saline and paraffin oil. Group 2 (hepatotoxic control) received TAA (300 mg/kg, once). Groups 3, 4, and 5 received TAA followed by vitamin E (100 mg/kg) and biopropolis (100 and 200 mg/kg), respectively, daily for 30 days. Evidences of HE were clearly detected in TAA-hepatotoxic group including significant elevation in the serum level of ammonia, liver functions, increased oxidative stress in liver and brain, apoptotic DNA fragmentation and overexpression of iNOS gene in brain tissue. The findings for groups administered biopropolis, highlighted its efficacy as a hepato- and neuro-protectant through improving the liver functions, oxidative status and DNA fragmentation as well as suppressing the brain expression of iNOS gene. In conclusion, biopropolis, at a dose of 200 mg/kg per day protected against TAA-induced HE through its antioxidant and antiapoptotic influence; therefore, it can be used as a protective natural product.

  10. Limited Link between Oxidative Stress and Ochratoxin A—Induced Renal Injury in an Acute Toxicity Rat Model

    Directory of Open Access Journals (Sweden)

    Liye Zhu

    2016-12-01

    Full Text Available Ochratoxin A (OTA displays nephrotoxicity and hepatotoxicity. However, in the acute toxicity rat model, there is no evidence on the relationship between OTA and nephrotoxicity and hepatotoxicity. Based on this, the integrated analysis of physiological status, damage biomarkers, oxidative stress, and DNA damage were performed. After OTA treatment, the body weight decreased and AST, ALP, TP, and BUN levels in serum increased. Hydropic degeneration, swelling, vacuolization, and partial drop occurred in proximal tubule epithelial cells. PCNA and Kim-1 were dose-dependently increased in the kidney, but Cox-2 expression and proliferation were not found in the liver. In OTA-treated kidneys, the mRNA expressions of Kim-1, Cox-2, Lcn2, and Clu were dose-dependently increased. The mRNA expressions of Vim and Cox-2 were decreased in OTA-treated livers. Some oxidative stress indicators were altered in the kidneys (ROS and SOD and livers (SOD and GSH. DNA damage and oxidative DNA damage were not found. In conclusion, there is a limited link between oxidative stress and OTA-induced renal injury in an acute toxicity rat model.

  11. Acute Appendicitis

    DEFF Research Database (Denmark)

    Tind, Sofie; Qvist, Niels

    2017-01-01

    and treatment of AA it is important that the classifications are consistent. Furthermore, in the clinical settings, incorrect classification might lead to over diagnosing and a prolonged antibiotic treatment. The aim of our study was to investigate the concordance between perioperative diagnosis made......BACKGROUND: The classification of acute appendicitis (AA) into various grades is not consistent, partly because it is not clear whether the perioperative or the histological findings should be the foundation of the classification. When comparing results from the literature on the frequency...

  12. Acute lower extremity ischaemia

    African Journals Online (AJOL)

    Acute lower extremity ischaemia. Acute lower limb ischaemia is a surgical emergency. ... is ~1.5 cases per 10 000 persons per year. Acute ischaemia ... Table 2. Clinical features discriminating embolic from thrombotic ALEXI. Clinical features.

  13. Acute kidney failure

    Science.gov (United States)

    ... Renal failure - acute; ARF; Kidney injury - acute Images Kidney anatomy References Devarajan P. Biomarkers for assessment of renal function during acute kidney injury. In: Alpern RJ, Moe OW, Caplan M, ...

  14. Preliminary studies on antihepatotoxic effect of Physalis peruviana Linn. (Solanaceae) against carbon tetrachloride induced acute liver injury in rats.

    Science.gov (United States)

    Arun, M; Asha, V V

    2007-04-20

    Physalis peruviana is a medicinal herb used by Muthuvan tribes and Tamilian native who reside in the shola forest regions of Kerala, India against jaundice. It was evaluated for its antihepatotoxic, phytochemical analysis and the acute toxicity of the most promising extract in rats. Water, ethanol and hexane extracts of Physalis peruviana (500mg/kg body weight) showed antihepatotoxic activities against CCl(4) induced hepatotoxicity. The ethanol and hexane extracts showed moderate activity compared to water extract, which showed activity at a low dose of 125mg/kg. The results were judged from the serum marker enzymes. Histopathological changes induced by CCl(4) were also significantly reduced by the extract. Further, the extract administration to rats resulted in an increase in hepatic GSH and decrease in MDA. Preliminary phytochemical analysis revealed the presence of various components in the crude aqueous extract. The extract was found to be devoid of any conspicuous acute toxicity in rats.

  15. Traditional Chinese Medicine (TCM) and Herbal Hepatotoxicity: RUCAM and the Role of Novel Diagnostic Biomarkers Such as MicroRNAs

    Science.gov (United States)

    Teschke, Rolf; Larrey, Dominique; Melchart, Dieter; Danan, Gaby

    2016-01-01

    Background: Traditional Chinese Medicine (TCM) with its focus on herbal use is popular and appreciated worldwide with increased tendency, although its therapeutic efficacy is poorly established for most herbal TCM products. Treatment was perceived as fairly safe but discussions emerged more recently as to whether herb induced liver injury (HILI) from herbal TCM is a major issue; Methods: To analyze clinical and case characteristics of HILI caused by herbal TCM, we undertook a selective literature search in the PubMed database with the search items Traditional Chinese Medicine, TCM, alone and combined with the terms herbal hepatotoxicity or herb induced liver injury; Results: HILI caused by herbal TCM is rare and similarly to drugs can be caused by an unpredictable idiosyncratic or a predictable intrinsic reaction. Clinical features of liver injury from herbal TCM products are variable, and specific diagnostic biomarkers such as microsomal epoxide hydrolase, pyrrole-protein adducts, metabolomics, and microRNAs are available for only a few TCM herbs. The diagnosis is ascertained if alternative causes are validly excluded and causality levels of probable or highly probable are achieved applying the liver specific RUCAM (Roussel Uclaf Causality Assessment Method) as the most commonly used diagnostic tool worldwide. Case evaluation may be confounded by inappropriate or lacking causality assessment, poor herbal product quality, insufficiently documented cases, and failing to exclude alternative causes such as infections by hepatotropic viruses including hepatitis E virus infections; Conclusion: Suspected cases of liver injury from herbal TCM represent major challenges that deserve special clinical and regulatory attention to improve the quality of case evaluations and ascertain patients’ safety and benefit. PMID:28930128

  16. Total glucosides of paeony can reduce the hepatotoxicity caused by Methotrexate and Leflunomide combination treatment of active rheumatoid arthritis.

    Science.gov (United States)

    Xiang, Nan; Li, Xiao-Mei; Zhang, Miao-Jia; Zhao, Dong-Bao; Zhu, Ping; Zuo, Xiao-Xia; Yang, Min; Su, Yin; Li, Zhan-Guo; Chen, Zhu; Li, Xiang-Pei

    2015-09-01

    Total glucosides of paeony (TGP) have been confirmed to exert anti-inflammatory and hepatoprotective effects. Methotrexate (MTX) and Leflunomide (LEF) combination has a better efficacy in the treatment of active rheumatoid arthritis (RA), but hepatotoxicity was observed. In this study, we investigated the effect of TGP on hepatic dysfunction caused by MTX and LEF in patients with active RA. A total of 268 patients with active RA (disease activity score in 28 joints, DAS28>3.2) were enrolled in this study. All patients were randomly assigned to two groups, the therapeutic group in which patients were treated with TGP (1.8 g/day) combined with MTX and LEF (MTX 10mg/week plus LEF 20mg/day) while in the control group, patients were treated without TGP up to 12 weeks. The efficacy and liver abnormalities were observed. The incidence of abnormal liver function within 12 weeks in TGP group was significantly lower than that in control group (11.38% vs 23.26%, P=0.013). The proportion of patients with ALT/AST >3 times ULN (upper limits of normal) was significantly lower in TGP group than control group (1.63% vs 7.75%, P=0.022). More patients achieved remission, good and moderate response in TGP group than control group at 4, 8 and 12 weeks, but the difference was not significant (P>0.05). The proportions of all adverse events were comparable in the two groups except for diarrhea. Our study demonstrates that TGP can significantly reduce the incidence and severity of liver damage caused by MTX+LEF in the treatment of active RA patients. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Traditional Chinese Medicine (TCM and Herbal Hepatotoxicity: RUCAM and the Role of Novel Diagnostic Biomarkers Such as MicroRNAs

    Directory of Open Access Journals (Sweden)

    Rolf Teschke

    2016-07-01

    Full Text Available Background: Traditional Chinese Medicine (TCM with its focus on herbal use is popular and appreciated worldwide with increased tendency, although its therapeutic efficacy is poorly established for most herbal TCM products. Treatment was perceived as fairly safe but discussions emerged more recently as to whether herb induced liver injury (HILI from herbal TCM is a major issue; Methods: To analyze clinical and case characteristics of HILI caused by herbal TCM, we undertook a selective literature search in the PubMed database with the search items Traditional Chinese Medicine, TCM, alone and combined with the terms herbal hepatotoxicity or herb induced liver injury; Results: HILI caused by herbal TCM is rare and similarly to drugs can be caused by an unpredictable idiosyncratic or a predictable intrinsic reaction. Clinical features of liver injury from herbal TCM products are variable, and specific diagnostic biomarkers such as microsomal epoxide hydrolase, pyrrole-protein adducts, metabolomics, and microRNAs are available for only a few TCM herbs. The diagnosis is ascertained if alternative causes are validly excluded and causality levels